Sundeep G Keswani

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (68)110.4 Total impact

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    ABSTRACT: Objective: The effect of chronic hyperglycemic exposure on endothelial cell (EC) phenotype, impaired wound neovascularization, and healing is not completely understood. The hypotheses are: 1) chronic exposure to diabetic conditions in vivo impairs the angiogenic potential of ECs and 2) this deficiency can be improved by an extracellular microenvironment of angiogenic peptide nanofibers. Approach: Angiogenic potential of microvascular ECs isolated from diabetic (db/db) and wild type (wt) mice was assessed by quantifying migration, proliferation, apoptosis, capillary morphogenesis, and vascular endothelial growth factor (VEGF) expression for cell cultures on Matrigel (Millipore, Billerica, MA) or nanofibers under normoglycemic conditions. The in vivo effects of nanofiber treatment on wound vascularization were determined using two mouse models of diabetic wound healing. Results: Diabetic ECs showed significant impairments in migration, VEGF expression, and capillary morphogenesis. The nanofiber microenvironment restored capillary morphogenesis and VEGF expression and significantly increased proliferation and decreased cell apoptosis of diabetic cells versus wt controls. In diabetic wounds, nanofibers significantly enhanced EC infiltration, neovascularization, and VEGF protein levels, as compared to saline treatment; this effect was observed even in MMP9 knockout mice with endothelial progenitor cell (EPC) deficiency. Innovation: The results suggest a novel approach for correcting diabetes-induced endothelial deficiencies via cell interactions with a nanofiber-based provisional matrix in the absence of external angiogenic stimuli. Conclusion: Impaired endothelial angiogenic potential can be restored by angiogenic cell stimulation in the nanofiber microenvironment; this suggests that nanofiber technology for diabetic wound healing and treatment of other diabetes-induced vascular deficiencies is promising.
    Advances in wound care. 11/2014; 3(11):717-728.
  • 2014 American Academy of Pediatrics National Conference and Exhibition; 10/2014
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    ABSTRACT: Objective To evaluate fetal lung growth rate for isolated left-sided CDH using serial MRI-based volumetric measures.Methods Early and late gestational (22-30 and > 30 weeks’ gestation) lung volumetry was obtained by fetal MRI in 47 cases of isolated left-sided CDH. At both of these time points, lung volume indices, including total lung volume (TLV), observed to expected TLV (o/e TLV), and percentage of predicted lung volume (PPLV) as well as their change rates (∆) and relative ∆ during gestation were calculated and analyzed in regard to their capacity to predict neonatal survival.ResultsTLV, o/e TLV, and PPLV had various changes during gestation. Late TLV, early and late o/e TLV, and late PPLV were predictive of neonatal survival. Non-survivors had lower ∆TLV and more negative relative ∆PPLV than survivors (1.18 mL/wk vs 1.85 mL/wk, P = 0.004 and -4.15 %/wk vs -1.95 %/wk, P = 0.002, respectively).Conclusions The severity of pulmonary hypoplasia is dynamic and can worsen in the third trimester. MRI lung volumetry repeated in late gestation can provide additional information on individual lung growth that may facilitate prenatal counseling and focus perinatal management. This article is protected by copyright. All rights reserved.
    Prenatal Diagnosis 10/2014; · 2.68 Impact Factor
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    ABSTRACT: Objective To determine whether fetal lung volume and visceral herniation are associated with changes in intrathoracic space in congenital diaphragmatic hernia(CDH).Methods We retrospectively examined the relationship between MRI-derived measurements of intrathoracic space (predicted lung volume (PLV)) and residual lung volume or visceral herniation among isolated left-sided CDH fetuses.ResultsData from fetal MRI studies of 60 isolated left-sided CDH cases were analyzed. The median PLV of the CDH fetuses was found to be much greater than the expected total lung volume(eTLV) of a normal fetus at the same gestational age. Surprisingly, liver herniation and observed TLV(oTLV) were positively correlated with the PLV. Although the PPLV was consistently less than the o/eTLV, both indices were greater in survivors than in non-survivors, whereas no significant difference was seen in the PLV/eTLV ratio in regard to survivorship.Conclusion The intrathoracic domain available for lungs and viscera is expanded in CDH fetuses and positively affected by the lung volume and the presence of liver herniation, leading to the difference in the PPLV and o/eTLV. Future study of intrathoracic space as it relates to the growth of the lung and herniated viscera is needed to better characterize the relationship between these parameters. This article is protected by copyright. All rights reserved..
    Prenatal Diagnosis 10/2014; · 2.68 Impact Factor
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    ABSTRACT: Significance: Revascularization plays a critical role in wound healing and is regulated by a complex milieu of growth factors and cytokines. Deficiencies in revascularization contribute to the development of chronic nonhealing wounds. Recent Advances: Stem-cell-based therapy provides a novel strategy to enhance angiogenesis and improve wound healing. With bioethical concerns associated with embryonic stem cells, focus has shifted to different populations of vascular precursors, isolated from adult somatic tissue. Three main populations have been identified: endothelial progenitor cells, mesenchymal stem cells, and induced-pluripotent stem cells. These populations demonstrate great promise to positively influence neovascularization and wound repair. Critical Issues: Further studies to more definitively define each population are necessary to efficiently translate stem-cell-based therapeutic angiogenesis to the bedside. Better understanding of the physiologic pathways of how stem cells contribute to angiogenesis in normal tissue repair will help identify targets for successful therapeutic angiogenesis. Future Directions: Active studies in both animal models and clinical trials are being conducted to develop effective delivery routes, including dosing, route, and timing. Stem-cell-based therapy holds significant potential as a strategy for therapeutic angiogenesis in the care of patients with chronic nonhealing wounds.
    Advances in wound care. 10/2014; 3(10):614-625.
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    ABSTRACT: The purpose of this study was to characterize the growth rate of sacrococcygeal teratomas (SCTs) and determine its relationship to adverse outcomes.
    Journal of Pediatric Surgery 06/2014; 49(6):985-9. · 1.38 Impact Factor
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    ABSTRACT: Significance: Postnatal wounds heal with characteristic scar formation. In contrast, the mid-gestational fetus is capable of regenerative healing, which results in wound repair that is indistinguishable from uninjured skin. However, the underlying mechanisms of fetal regenerative phenotype are unknown. Recent Advances: The potent anti-inflammatory cytokine, interleukin-10 (IL-10), plays an essential role in the ability of the fetus to heal regeneratively and has been shown to recapitulate scarless healing in postnatal tissue. IL-10's ability to facilitate regenerative healing is likely a result of pleiotropic effects, through regulation of the inflammatory response, as well as novel roles as a regulator of the extracellular matrix, fibroblast cellular function, and endothelial progenitor cells. Overexpression of IL-10 using a variety of methods has been demonstrated to recapitulate the fetal regenerative phenotype in post-natal tissue, in conjunction with promising results of Phase II clinical trials using recombinant IL-10. Critical Issues: Successful wound healing is a complex process that requires coordination of multiple growth factors, cell types, and extracellular cellular matrix components. IL-10 has been demonstrated to be critical in the fetus' intrinsic ability to heal without scars, and, further, can induce scarless healing in postnatal tissue. The mechanisms through which IL-10 facilitates this regeneration are likely the result of IL-10's pleiotropic effects. Efforts to develop IL-10 as an anti-scarring agent have demonstrated promising results. Future Directions: Further studies on the delivery, including dose, route, and timing, are required in order to successfully translate these promising findings from in vitro studies and animal models into clinical practice. IL-10 holds significant potential as an anti-scarring therapeutic.
    Advances in wound care. 04/2014; 3(4):315-323.
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    ABSTRACT: 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. 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 × 10(8) 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. 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. 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.
    Journal of Surgical Research 03/2014; · 2.02 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Journal of Surgical Research 02/2014; · 2.02 Impact Factor
  • Alice King, Sundeep G. Keswani
    Journal of Surgical Research 01/2014; 186(1):87–88. · 2.02 Impact Factor
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    ABSTRACT: Chylothorax is a frequent complication in congenital diaphragmatic hernia (CDH) infants and is associated with significant morbidity. The optimal treatment strategy remains unclear. We hypothesize that octreotide decreases chylous effusions in infants with CDH. This is a retrospective study of all infants with CDH admitted to our institution from October 2006 to October 2011. Eleven (12%) infants developed a chylothorax. Five infants were managed conservatively with thoracostomy and total parenteral nutrition. Six infants were started on octreotide therapy. None of the infants required surgical intervention to stop the effusion. There was no significant difference in survival to discharge, length of stay, or average daily chest tube output between groups. There appeared to be a temporally associated drop in chest tube output upon initiation of octreotide in two infants; however, the overall rate of decline in chest tube drainage was unchanged. In addition, there were infants in the conservative group who demonstrated a similar drop in daily chest tube output despite the absence of octreotide. Our data suggest that the majority of chylous effusions in CDH infants resolve with conservative therapy alone.
    Journal of Pediatric Surgery 11/2013; 48(11):2226-9. · 1.38 Impact Factor
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    ABSTRACT: Recapitulating Fetal "Scarless" Healing In Postnatal Wounds: Are We There Yet? Purpose Mid-gestation fetal skin heals wounds without scar. We have identified an essential role of IL-10 in the fetus' ability to heal regeneratively and have demonstrated that viral mediated IL-10 overexpression results in regenerative wound healing in postnatal wounds. Given the inherent translational issues with viral-mediated gene therapy, we aim to validate a clinically translatable hydrogel delivery system of IL-10, which will result in fetal-type regenerative healing. Methods We first determined the optimal hydrogel composition for sustained IL-10 release kinetics. The composition of thiol-modified hyaluronan with thiol-modified heparin (HA), thiol-modified gelatin and a thiol-reactive crosslinker (polyethylene glycol diacrylate, PEGDA) were tested. The following ratios of HA:Gelatin:PEGDA were loaded with IL-10 (800 ng/25 ul) and evaluated: 1) Gel A (2:2:1), 2) Gel B (2:1:1), 3) Gel C (0:1:0) (thiol-modified gelatin only), 4) Gel D (0:0:1) (PEGDA only). Daily release of IL-10 was evaluated for seven days (ELISA). Identifying the hydrogels capable of sustained release, we then evaluated 4-mm excisional wounds in vivo. Wounds were treated with the hydrogel+IL-10, hydrogel control or recombinant IL-10 control and evaluated at 28 days (H&E). Results In vitro, all four hydrogel demonstrated release of IL-10 for three days. While hydrogels containing HA (Gel A and Gel B) continued sustained release of IL-10 for seven days, Gel C and Gel D release decreases at day 4 (<20 pg/ml) (Figure 1). All wounds re-epithelialized with no apparent differences in cellular infiltrate. In vivo, Gel A+IL-10 (Figure 2A) demonstrated scar attenuation with modulation of the dermal matrix with a more basket-weave pattern compared to both Gel A (Figure 2B) or recombinant IL-10 alone (Figure 2C). Gel B+IL-10 results in regeneration of native matrix with dermal appendages (Figure 2D) compared to Gel B control or recombinant IL-10. Gel B control results in remodeling of dermal matrix at the periphery of wound edges with a more basket-weave pattern matrix (Figure 2E) compared to IL-10 alone and absence of dermal appendages. Single administration of recombinant IL-10 results in characteristic post-natal scar formation, with thick, parallel bundles and absence of dermal appendages (Figure 2C,F). Conclusion We have optimized an innovative IL-10 hydrogel delivery system that, with a single topical application, results in regenerative wound healing that is indistinguishable from surrounding skin. This work has significant clinical translatability and the potential to realize the goal of recapitulating the fetal regenerative phenotype. Lastly, these data have implications beyond cutaneous wound healing and may be applicable to any disease process characterized by excessive fibroplasia. Figure 1 Figure 2
    2013 American Academy of Pediatrics National Conference and Exhibition; 10/2013
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    ABSTRACT: In utero hematopoietic cellular transplantation (IUHCT) holds great promise for the treatment of congenital diseases of cellular dysfunction such as sickle cell disease, immunodeficiency disorders and inherited metabolic disorders. However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a closer examination of the fetal immune system. While the mechanisms regulating T cell tolerance have been previously studied, the educational mechanisms leading to NK cell tolerance in prenatal chimeras remain unknown. As a low level of donor cells (1.8%) is required to induce and maintain this tolerance, it is likely that these mechanisms employ indirect host-donor interaction. This report examines donor-to-host MHC transfer (trogocytosis) as an intrinsic mechanism regulating the development and maintenance of NK cell tolerance in prenatal chimeras. The findings demonstrate that phenotypically tolerant host NK cells express low levels of transferred donor MHC antigens during development and later as mature cytotoxic lymphocytes. Further study is needed to understand how the cis-recognition of transferred donor MHC ligand influences the selection and maintenance of tolerant NK cells in prenatal chimeras.
    Chimerism. 10/2013; 4(4).
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    ABSTRACT: Postnatal vasculogenesis mediated via endothelial progenitor cells (EPCs) contributes to re-endothelialization and augments neovascularization after ischemia and tissue injury, providing a novel therapeutic application. However, controversy exists with respect to the origin, identification, and contributions of the EPCs to neovascularization, necessitating further study. Bone marrow (BM) or circulating cells expressing cd133/vascular endothelial growth factor receptor 2 include those with endothelial progenitor capacity. Increasing evidence suggests that there are additional BM-derived (myeloid; mesenchymal cells) and non-BM-derived (peripheral and cord-blood; tissue-resident) cell populations which also give rise to endothelial cells (ECs) and contribute to re-endothelialization and growth factor release after ischemia and tissue injury. Currently, EPCs are being used as diagnostic markers for the assessment of cardiovascular and tumor risk/progression. Techniques aimed at enhancing ex vivo expansion and the therapeutic potential of these cells are being optimized. Mobilization and EPC-mediated neovascularization are critically regulated. Stimulatory (growth factors, statins, and exercise) or inhibitory factors (obesity, diabetes, and other cardiovascular diseases) modulate EPC numbers and function. Recruitment and incorporation of EPCs require a coordinated sequence of signaling events, including adhesion, migration (by integrins), and chemoattraction. Finally, EPCs differentiate into ECs and/or secrete angiogenic growth factors. These cells are highly plastic, and depending on the microenvironment and presence of other cells, EPCs transdifferentiate and/or undergo cell fusion and become cells of a different lineage. Therefore, in vitro culture conditions should be optimized to mimic the in vivo milieu to fully characterize the biological function and contribution of EPCs to postnatal vasculogenesis. Advances in characterization of the EPC biology and enhancement of EPC functions are required. In addition, innovative tissue-engineered carrier matrices that permit embedding of EPCs and provide optimal conditions for EPC survival and endothelial outgrowth will further contribute to EPC-mediated therapeutic applications in wound healing and ischemia repair.
    Advances in wound care. 07/2013; 2(6):283-295.
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    ABSTRACT: BACKGROUND: Sacrococcygeal teratoma (SCT) is one of the most common neonatal and fetal tumors. SCT pelvic mass effect and the need for aggressive surgical resection, create potential for urologic co-morbidity. We reviewed our experience with SCTs and propose a rational plan for urologic surveillance. METHODS: We retrospectively reviewed all patients with SCT evaluated at our institution from 2004 to 2011. We collected data on the need for reconstructive surgery related to the urologic co-morbidity, the time to detection of urologic co-morbidity, and length of follow-up. RESULTS: We identified 28 patients evaluated during the study period with a median follow-up of 3.1 year (range 0.14-13.4). The Altman classifications were-type I: 7 (25%), II: 15 (53.6%), and III: 6 (21.4%). Eighteen (64.3%) patients had an associated urologic co-morbidity: 12 (42.9%) patients had hydronephrosis, VUR-10 (35.7%), NGB-13 (46.4%), and 4 (14.3%) developed ≥CKD2. When comparing the patients according to Altman classification, there was a trend towards more urologic co-morbidity in patients with increasing pelvic involvement, P = 0.06. Eleven patients (39.3%) had delayed urologic evaluation and five (17.9%) required reconstructive urologic surgery. In comparing these groups, 4 of 11 (36.4%) undergoing delayed urologic evaluation progressed to reconstruction, as opposed to only one of 17 (5.7%) with urologic evaluation within first year of life (P-value = 0.06). CONCLUSION: Urologic co-morbidities are common in children with SCT and appear most common in patients with more pelvic tumor involvement (≥Altman II). A risk-adapted approach to urologic surveillance is proposed. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 06/2013; · 2.35 Impact Factor
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    ABSTRACT: The mucosa of alimentary tract heals more rapidly than cutaneous wounds. The underlying mechanisms of this enhanced healing have not been completely elucidated. Constant exposure to salivary growth factors has been shown to play a critical role in mucosal homeostasis and tissue repair. Angiogenesis also has an essential role in successful wound repair. One of the main angiogenic growth factors, vascular endothelial growth factor (VEGF), has a pleiotropic role in tissue repair via neovascularization, reepithelialization, and regulation of extracellular matrix. We have previously reported a critical role for salivary VEGF in bowel adaptation after small bowel resection. We hypothesize that salivary VEGF is an essential stimulus for oral mucosal tissue repair, and use the murine palatal wound model to test our hypothesis. In a loss-of-function experiment, we removed the primary source of VEGF production through selective submandibular gland (SMG) sialoadenectomy in a murine model and observed the effects on wound closure and neovascularization. We then performed a selective loss-of-function experiment using the protein VEGF-Trap to inhibit salivary VEGF. In a gain-of-function experiment, we supplemented oral VEGF following SMG sialoadenectomy. After SMG sialoadenectomy, there was significant reduction in salivary VEGF level, wound closure, and vessel density. Lower levels of salivary VEGF were correlated with impaired neovascularization and reepithelialization. The selective blockade of VEGF using VEGF-Trap resulted in a similar impairment in wound healing and neovascularization. The sole supplementation of oral VEGF after SMG sialoadenectomy rescued the impaired wound healing phenotype and restored neovascularization to normal levels. These data show a novel role for salivary-VEGF in mucosal wound healing, and provide a basis for the development of novel therapeutics aimed at augmenting wound repair of the oral mucosa, as well as wounds at other sites in the alimentary tract.
    Wound Repair and Regeneration 06/2013; · 2.76 Impact Factor
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    ABSTRACT: Mid-gestational (E14.5) fetal wounds heal regeneratively with attenuated inflammation and high levels of hyaluronan (HA) in their extracellular matrix (ECM), whereas late-gestational (E18.5) fetal wounds heal with scarring. IL-10 plays an essential role in the fetal regenerative phenotype and is shown to recapitulate scarless wound healing postnatally. We hypothesize a novel role of IL-10 as a regulator of HA in the ECM. Murine fetal fibroblasts (FFb) from C57Bl/6 and IL-10-/- mice were evaluated in vitro. Pericellular matrix (PCM) and HA synthesis were quantified using a particle exclusion assay and ELISA. The effects of hyaluronidase and hyaluronan synthase (HAS) inhibitor (4-methylumbelliferone[4-MU]) were evaluated. An ex vivo fetal forearm culture incisional wound model comparing mid-gestation and late-gestation fetuses was used to evaluate IL-10's effect on HA-rich ECM production with pentachrome and immunohistochemistry. FFb produce a robust HA-rich PCM which is IL-10 dependent and attenuated with hyaluronidase and HAS inhibition. Mid-gestation fetal wounds produce more ground substance and HA than late-gestation fetal wounds. IL-10 in late-gestation fetal wounds results in elevated ground substance levels and HA staining. Our data demonstrate that IL-10 regulates an HA-rich ECM deposition, suggesting a novel non-immunoregulatory mechanism of IL-10 in mediating regenerative wound healing.
    Journal of Pediatric Surgery 06/2013; 48(6):1211-1217. · 1.38 Impact Factor
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    ABSTRACT: BACKGROUND: Sacrococcygeal teratoma is the most common neonatal tumor. Fetuses with large tumors may develop hydrops from a high cardiac output state (HCOS) and progress rapidly to fetal demise. We postulate that the prenatal solid tumor volume index (STVI), or the ratio of solid tumor volume to the estimated fetal weight (EFW), has greater impact than the total tumor volume in outcome prediction. METHODS: A retrospective chart review of all sacrococcygeal teratoma patients (n = 38) between 2005 and 2012 was conducted. Total tumor volume and percent of solid component were calculated by magnetic resonance imaging and then normalized by dividing them by either head circumference or EFW. Outcomes measured were survival, hydrops or high cardiac output state, defined as a combined ventricular output of >625 mL/min/kg with abnormal Doppler or echocardiogram findings. RESULTS: Thirty-one patients were included in the study. All deaths (n = 7) had either high cardiac output state or hydrops. At a total tumor volume/EFW >0.16, the patient was 17 times more likely to develop HCOS/hydrops (P = 0.001) with 81.25% sensitivity and 86.67% specificity. At a STVI >0.09, the patient was 120 times more likely to develop HCOS/hydrops (P < 0.0001) with 81.25% sensitivity and 100% specificity. CONCLUSIONS: While total tumor volume aids in stratifying patients into high risk categories, STVI (solid tumor volume/EFW) is a better predictor of adverse outcomes. This data will allow us to identify patients who are high risk for cardiac compromise and guide appropriate therapy.
    Journal of Surgical Research 05/2013; · 2.02 Impact Factor
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    ABSTRACT: BACKGROUND AND OBJECTIVE:Pediatric patients are at risk for developing pressure ulcers (PUs) and associated pain, infection risk, and prolonged hospitalization. Stage III and IV ulcers are serious, reportable events. The objective of this study was to develop and implement a quality-improvement (QI) intervention to reduce PUs by 50% in our ICUs.METHODS:We established a QI collaborative leadership team, measured PU rates during an initial period of rapid-cycle tests of change, developed a QI bundle, and evaluated the PU rates after the QI implementation. The prospective study encompassed 1425 patients over 54 351 patient-days in the PICU and NICU.RESULTS:The PU rate in the PICU was 14.3/1000 patient-days during the QI development and 3.7/1000 patient-days after QI implementation (P < .05), achieving the aim of 50% reduction. The PICU rates of stages I, II, and III conventional and device-related PUs decreased after the QI intervention. The PU rate in the NICU did not change significantly over time but remained at a mean of 0.9/1000 patient-days. In the postimplementation period, 3 points were outside the control limits, primarily due to an increase in PUs associated with pulse oximeters and cannulas.CONCLUSIONS:The collaborative QI model was effective at reducing PUs in the PICU. Pediatric patients, particularly neonates, are at risk for device-related ulcers. Heightened awareness, early detection, and identification of strategies to mitigate device-related injury are necessary to further reduce PU rates.
    PEDIATRICS 05/2013; · 4.47 Impact Factor
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    ABSTRACT: BACKGROUND: The midgestational fetus is capable of regenerative healing. We have recently demonstrated a novel role for the anti-inflammatory cytokine interleukin 10 (IL-10) as a regulator of hyaluronan (HA) in the extracellular matrix. The signaling pathway of IL-10 has been studied in monocytes but is unknown in dermal fibroblasts. We hypothesized IL-10 signals through its primary receptor, IL-10R1, to activate STAT3, resulting in HA synthesis. METHODS: Murine midgestational (E14.5) fetal fibroblasts were evaluated in vitro. Pericellular matrix was quantified using a particle exclusion assay. STAT3 levels and cellular localization were evaluated by Western blot/band densitometry and immunocytochemistry/confocal microscopy. HA levels were quantified by enzyme-linked immunosorbent assay. The effects of IL-10R1 signal blockade by a neutralizing antibody and STAT3 inhibition were evaluated. An ex vivo midgestation fetal forearm culture incisional wound model in control and transgenic IL-10-/- mice was used to evaluate the role of STAT3 on the extracellular matrix. RESULTS: Fetal fibroblasts produce a robust hyaluronan-rich pericellular matrix that is IL-10R1 and STAT3 dependent. Inhibition of IL-10R1 signaling results in decreased phosphorylated STAT3 levels and inhibition of nuclear localization. Inhibition of STAT3 results in decreased HA production. At day 3, midgestation fetal wounds have efficient re-epithelialization, which is significantly slowed in IL-10-/- wounds at the same gestation and with inhibition of STAT3. CONCLUSIONS: Our data demonstrate that IL-10 regulates HA synthesis through its primary receptor IL-10R1 and STAT3 activation. This supports a novel nonimmunoregulatory mechanism of IL-10 in its role in fetal regenerative wound healing.
    Journal of Surgical Research 04/2013; · 2.02 Impact Factor

Publication Stats

313 Citations
110.40 Total Impact Points

Institutions

  • 2007–2014
    • Cincinnati Children's Hospital Medical Center
      • Division of Pediatric General and Thoracic Surgery
      Cincinnati, Ohio, United States
  • 2004–2014
    • University of Cincinnati
      • College of Medicine
      Cincinnati, Ohio, United States
  • 2003–2013
    • The Children's Hospital of Philadelphia
      • Children's Institute for Surgical Science
      Philadelphia, Pennsylvania, United States
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2002
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Surgery
      Baton Rouge, LA, United States