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Biomedical subjects

George K Gittes

Publications and source records attributed to George K Gittes.

At least 19 recordsLinked to original sources
PubMed2006

Relative value units correlate with pediatric surgeons' operating time: when perceived myth becomes reality.

PURPOSE: In 1992, the Congress implemented a Medicare payment system based on relative value units (RVUs). Today, RVUs are increasingly used to determine surgeon reimbursement from Medicare, Medicaid, and private third-party payers. We questioned whether current RVU assignments accurately reflect the quantity of time that surgeons spend operating. METHODS: Over a 12-month period, 59 common pediatric operations were identified and classified as general surgery (n = 34), urology (n = 13), or minimally invasive (n = 10). Only operations performed as an outpatient or requiring less than one inpatient day of direct surgeon involvement were included. By regression analysis, correlation coefficients were generated comparing average operating time per procedure to the corresponding RVU generated. RESULTS: Of 59 specific operations, a total of 744 general surgery cases, 1155 urological cases, and 370 minimally invasive cases were performed. RVU efficiency was greatest in general surgery (1 RVU = 5.18 operating minutes), followed by minimally invasive operations (1 RVU = 6.80 minutes) and urological operations (1 RVU = 8.59 minutes). Regression analysis proved minimally invasive operations to correlate best with RVUs with R2 = 0.8376, followed by urology at R2 = 0.6753, and then general surgery at R2 = 0.649. CONCLUSIONS: The RVU has emerged as the most dominant factor influencing reimbursement of practicing pediatric surgeons. Despite common surgeon bias, RVUs do correlate with current operating times. These data prove important as surgeons analyze cost, negotiate contracts, and strategically plan for fiscal success.

Child↗
PubMed2006

Faulty bone morphogenetic protein signaling in esophageal atresia with tracheoesophageal fistula.

BACKGROUND: The organogenesis of esophageal atresia with tracheoesophageal fistula remains unclear. We have previously demonstrated that the fistula tract develops from a trifurcation of the embryonic lung bud and displays pulmonary lineage traits. Unlike the lung, the fistula grows without branching. Bone morphogenetic proteins (BMPs) are known to be important in lung branching. We studied possible BMP signaling defects as a potential cause for the absence of branching in the fistula tract. METHODS: Adriamycin was administered to pregnant rats on days 6-9 of gestation to induce tracheoesophageal fistula. Microdissection was performed at E13 and E17 isolating the foregut. Tissues were analyzed using immunohistochemistry for BMP ligand (BMP2, BMP4, BMP7) and receptor (BMPRIA, BMPRIB, BMPRII) expression. RESULTS: Immunohistochemistry revealed the presence of all 3 BMP ligands at E13, localized specifically to the esophageal mucosa but absent in the fistula and lung. At E17, the ligands were again present in the esophageal mucosa, and additionally in the fistula tract mucosa, but remained absent in the lung. At E17, all of the BMP receptors were also localized to the luminal surface of esophagus and fistula. However, in the lung epithelium, only BMPRII was found, whereas BMPRIA and BMPRIB remained absent. CONCLUSIONS: The normal expression pattern of BMP4 was increased at the branch tips and low between branches. Among other results, we show here a constant expression level of BMP ligands throughout the entire epithelium of the fistula tract. This diffuse expression suggests defective BMP signaling in the fistula tract and explains its nonbranching phenotype.

Abnormalities, Drug-Induced↗
PubMed2006

Mesenchymal epimorphin is important for pancreatic duct morphogenesis.

Epithelial-mesenchymal interactions are crucial for the proper development of many organs, including the pancreas. Within the pancreas, the ducts are thought to harbor stem/progenitor cells, and possibly to give rise to pancreatic ductal carcinoma. Little is known about the mechanism of formation of pancreatic ducts in the embryo. Pancreatic mesenchyme contains numerous soluble factors which help to sustain the growth and differentiation of exocrine and endocrine structures. Here, we report that one such morphoregulatory mesenchymal protein, epimorphin, plays an important role during pancreatic ductal proliferation and differentiation. We found that epimorphin is expressed in pancreatic mesenchyme during early stages of development, and at mesenchymal-epithelial interfaces surrounding the ducts at later stages. Strong upregulation of epimorphin expression was seen during in vitro pancreatic duct differentiation. Similarly, in vitro pancreatic duct formation was inhibited by a neutralizing antibody against epimorphin, whereas addition of recombinant epimorphin partially rescued duct formation. Together, our study demonstrates the role of epimorphin in pancreatic ductal morphogenesis.

Animals↗
PubMed2005

Bone morphogenetic protein expression patterns in human esophageal atresia with tracheoesophageal fistula.

The organogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) remains unknown. The fistula tract appears to develop from a non-branching trifurcation of the embryonic lung bud. The non-branching growth of the fistula differs from the other lung buds and suggests a deficiency in bone morphogenetic protein (BMP) signaling, since BMPs are critical to proper lung development and branching. With IRB approval, portions of newborn human proximal esophageal pouch and distal fistula samples were recovered at the time of surgical repair of EA/TEF. The tissues were processed for immunohistochemistry. Commercially available fetal tissues were used as controls. In control tissues, BMP ligands (BMP 2, 4, and 7) were all present in the esophagus but absent in the trachea. BMPRIA was absent in both tissues. BMPRIB was detected in trachea but not in esophagus and BMPRII was detected in esophagus but not in trachea. In the EA/TEF specimens, all BMP ligands were present in the proximal esophageal pouch but absent in the fistula tract. BMPRIA and BMPRIB were not detected in either tissue. However, BMPRII was found in both fistula tract and proximal pouch. The submucosa of the fistula appears to maintain a mixed (identical neither to lung, esophagus, or trachea) BMP signaling pattern, providing one mechanism which could potentially explain the esophageal dismotility and lack of lung branching seen in the fistula/distal esophagus.

Bone Morphogenetic Protein Receptors, Type I↗
PubMed2005

Pancreatic differentiation.

Over the last decade, with the advent of new techniques and technologies in modern molecular biology, our understanding of the underlying mechanisms responsible for organ differentiation has developed rapidly. Despite this, our knowledge of these signaling pathways is still far from complete. Some of these advances, such as the creation of transgenic mouse models, have given us new tools to help us understand the interactions of the various transcription factors that are responsible for the creation of various cell types from a single cell type during embryogenesis. This knowledge then gives rise to the concept of creating new ways to manipulate stem cells in order to correct the deficiencies present in various disease processes. Here, we present work that focuses specifically on pancreatic development. The ultimate goal of our research in studying the mechanisms of the basic differentiation of pancreatic precursor cells is to gain the knowledge necessary to be able to engineer stem cells specifically into beta-cells in the treatment of diabetes.

Cell Differentiation↗
PubMed2005

Management of postoperative infections after the minimally invasive pectus excavatum repair.

PURPOSE: Pectus excavatum is frequently repaired using the minimally invasive placement of a substernal bar (Nuss procedure). Infectious complications after the Nuss procedure are potentially devastating. To date, the management of postoperative infectious complications has not been well described. METHODS: A retrospective review of all patients (N = 168) who underwent the Nuss procedure from January 1, 1997, to October 1, 2003, at our institution was performed. Six patients (4%) had postoperative infections, and their medical records were reviewed. RESULTS: Of the 6 patients, 5 underwent operative drainage for wound abscesses that developed 2 to 76 weeks postoperatively. The other patient developed cellulitis 12 months postoperatively and was treated effectively with antibiotics alone. Recurrent infections were treated in 3 of 6 patients, one of whom eventually required removal of the bar resulting in a mild, residual pectus excavatum defect. One of 6 patients has had the substernal bar removed electively. The remaining 4 continue to be without clinically apparent infection at this time and are over 1 year removed from their infection. CONCLUSIONS: Although uncommon, infectious complications after the Nuss procedure require complex management strategies. Despite recurrent infection in some cases, most infectious complications occurring after the minimally invasive repair can be effectively treated without having to remove the substernal bar.

Abscess↗
PubMed2005

Urachal anomalies in children: the vanishing relevance of the preoperative voiding cystourethrogram.

PURPOSE: Children with a wet, draining, or infected umbilicus are often referred to pediatric surgeons. Unfortunately, uniform guidelines regarding diagnostic imaging are lacking. Historically, the persistence of the urachus was attributed to intrauterine distal urinary obstruction. Today, many surgeons continue to advocate preoperative voiding cystourethrogram (VCUG). METHODS: Records of children with urachal abnormalities over the past 10 years were reviewed. Demographics, presentation, imaging, genitourinary anomalies, operations, length of stay, and complications were recorded. Statistical evaluation was by descriptive analysis. RESULTS: Fifty-six children were diagnosed with urachal anomalies. Age at operation was 2.5 years (1 day-13 years). Fifty percent of patients were less than 1 year. Ultrasound was used in 88% of cases. Voiding cystourethrogram (34%) and computed tomography (14%) were also used. Average hospitalization was 1.9 (0-13) days. Thirty-two percent underwent operations as outpatients. Seven percent developed wound infections. Eight children (14%) had genitourinary anomalies. However, no VCUG examination (n = 19) documented an obstructive process. CONCLUSIONS: The current study represents the largest reported series of symptomatic urachal anomalies in children. Disorders of the urachus are variable in presentation with the diagnosis reliably made by history and ultrasound alone. Further testing, including VCUG, is not warranted, adding additional cost, an invasive procedure, and inconvenience to the child.

Adolescent↗
PubMed2005

Pancreatic epithelial cells can be converted into insulin-producing cells by GLP-1 in conjunction with virus-mediated gene transfer of pdx-1.

BACKGROUND: Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion and proliferation by islet cells in vitro and in vivo, associated with an activation of pancreatic duodenal homeobox gene-1 (pdx-1) function. The effect of GLP-1 on the conditionally immortalized pancreatic epithelial cells (IMPE cells) is not clear when they are treated in conjunction with the adenovirus-mediated gene transfer of pdx-1. METHODS: IMPE cells were established from the pancreas of H-2K(b)-tsA58 transgenic mice. IMPE cells were maintained at 33 degrees C with 10 U/mL interferon (IFN)-gamma and the experiments were performed at 39 degrees C without IFN-gamma. IMPE cells were infected with 20 multiplicities of Ad-pdx-1 or control Ad-lacZ at 39 degrees C without IFN-gamma and were incubated with various concentrations of GLP-1. After 48 hours, immunofluorescence and reverse transcriptase-polymerase chain reaction for insulin and pdx-1 expression were examined. Immunoreactive insulin in the cell lysate and supernatant was also analyzed. The glucose concentration in the culture medium was changed to test the insulin secretory responsiveness of the IMPE cells. RESULTS: The treatment with GLP-1 in conjunction with Ad-pdx-1 induced insulin production by IMPE cells, but the treatment with either GLP-1 or Ad-pdx-1 alone failed to induce insulin production. Insulin production and secretion were increased by GLP-1 and by glucose in a dose-dependent manner. In addition, the insulin-producing IMPE cells acquired a rapid insulin secretory responsiveness to the changes of extracellular glucose concentration. CONCLUSIONS: GLP-1 and pdx-1 work together to induce insulin-producing cells from IMPE cells, which bear unique characteristics of pancreatic ductal cells. The results suggest that GLP-1 may be another important determiner of pancreatic endocrine differentiation as is pdx-1.

Adenoviridae↗
PubMed2005

Management of complications after hypospadias repair.

OBJECTIVES: To review our experience with hypospadias complications (seen after 10%-15% of repairs) and to identify factors influencing outcome. METHODS: We reviewed the available medical records of 113 patients who underwent repeat operation for hypospadias complications. Of the 113 patients, 40% had undergone the initial repair at our institution (internal referral); 60% had undergone the initial repair elsewhere before referral (external referral). The variables potentially affecting outcome were reviewed, including the severity of the defect, concomitant disease, age at the initial operation and revisions, type of complications and treatment, and the number of revisions. Outcomes were compared on the basis of specialty and experience. RESULTS: Isolated hypospadias was present in 81% and other genitourinary abnormalities in 10%. External referral patients were older at the first revision (7.3 versus 4.2 years, P = 0.027). Complications included fistula (73%), stricture (12%), breakdown of repair (10%), and diverticulum formation (11%). Successful revision was independent of the initial defect. The first, second, and third revision was successful in 77%, 64%, and 67% of patients, respectively. The cumulative success rate was 77%, 92%, and 97% after each respective repair attempt. The success of the repair was independent of the patient's age at the initial operation/revision and of the interval from the initial repair to reoperation. Internal referral and external referral patients had similar results. Specific experience with the repair of hypospadias complications correlated with a successful outcome (P <0.001). CONCLUSIONS: Complications after hypospadias repairs are common, with fistula accounting for approximately 75%. The outcome in our series was independent of hypospadias severity, patient age at repair, number of revisions, stent use, and referral status. Repairs performed by an experienced pediatric urologist were associated with improved outcomes (P <0.001).

Child↗
PubMed2005

Synergistic endocrine induction by GLP-1 and TGF-beta in the developing pancreas.

OBJECTIVES: Glucagon-like peptide-1 (GLP-1) is known to stimulate glucose-dependent insulin production and secretion by pancreatic beta-cells. Preliminary evidence suggests that GLP-1 may also influence endocrine differentiation from pancreatic progenitor cells. Additionally, TGF-beta signaling can also control endocrine differentiation by both inhibiting proliferation and enhancing differentiation of endocrine progenitor cells to become mature beta-cells. Here we document synergy of these two signaling pathways in the differentiation of endocrine cells in the developing pancreas. METHODS: Embryonic pancreas was harvested from mice at day 11.5 and cultured for six days with GLP-1 agonist, exendin-4, and/or TGF-beta1 ligand. Also, a pan-neutralizing TGF-beta isoform antibody was used alone or with exendin-4 to study TGF-beta inhibition in this system. Pancreatic cultures were processed for immunohistochemistry. RESULTS: Exogenous TGF-beta1 and exendin-4 each individually enhanced both insulin and glucagon differentiation dose-dependently. However, when combined there was an additive effect to a 4.5-fold increase in insulin-positive differentiation. We also saw suppression of amylase-positive differentiation. Surprisingly, TGF-beta pan-neutralizing antibody also gave an augmentation of endocrine differentiation by 1.5 to 2-fold, but no synergistic effect was seen with exendin-4. CONCLUSION: We conclude that TGF-beta isoforms have a specific synergistic role with GLP-1 pathway signaling in early pancreatic development, toward endocrine differentiation and away from acinar differentiation.

Animals↗
PubMed2004

Multifaceted pancreatic mesenchymal control of epithelial lineage selection.

Mouse pancreatic development is critically dependent on epithelial-mesenchymal interactions. The pancreas differs from other epithelial-mesenchymal organs in that the epithelium gives rise to both epithelial exocrine cells and non-epithelial endocrine cells. We studied the nature of the interactions between the epithelium and mesenchyme with respect to the decision between exocrine and endocrine lineages. We show here a tripartite influence of mesenchyme on the developing epithelium. First, close proximity or contact of mesenchyme with the epithelium induces exocrine differentiation. Second, this mesenchymal proximity to the epithelium suppresses endocrine differentiation. Third, mesenchyme has an overall enhancing effect on the degree of insulin differentiation, suggesting a pro-endocrine effect in those epithelial cells at a distance from the mesenchyme. Proximity or contact between the mesenchyme and epithelium appeared to be necessary for the pro-exocrine effects of mesenchyme. We found that, in a co-culture system, NIH3T3 cells were able to substitute for mesenchyme in exocrine induction as well as in both the endocrine induction and endocrine inhibition, implying that the responsible molecules are not unique to pancreatic mesenchyme. Laminin appears to be a key molecule mediating the epithelial-mesenchymal interactions that lead to exocrine differentiation, since inhibition of laminin expression resulted in blockage of the pro-exocrine induction of mesenchyme.

Animals↗
PubMed2004

Thyroglossal duct infections and surgical outcomes.

PURPOSE: Thyroglossal duct cysts (TGDC) are the most common head and neck congenital anomalies in children and often present as infected neck masses. The authors reviewed their experience with TGDC to determine if preoperative infection was related to postoperative complications, including recurrence and postoperative infection. METHODS: The medical records of 99 patients undergoing excision of TGDC from January 1991 to July 2002 were reviewed. Factors thought to be associated with recurrence (age, history of infection, drainage, abscess, and operative procedure) were analyzed. RESULTS: Ninety-nine patients made up the study group. The mean age at operation was 5.0 years (range, 6 months to 16 years) with a male to female ratio of 1.6:1. TGDC recurred in 12.1% (12 of 99) of these patients. There was no gender difference for those with and without recurrence. The presence of an abscess or cellulitis preoperatively (22 of 99 patients) did not correlate with recurrence (NS). In addition, postoperative infection occurred in 13 of 99 patients and also was independent of preoperative infection. However, postoperative infection clearly was associated with an increased risk of TGDC recurrence. Seven of 87 patients without recurrence had a postoperative infection, whereas 6 of 12 of those who had a recurrence had a postoperative infection (P <.001). The mean follow-up was 3.7 years and was comparable for the 2 groups (recurrence v. resolution). Twelve patients successfully underwent a second procedure for recurrence. CONCLUSIONS: In this large series of TGDC, preoperative infection occurred in approximately 1 of 5 patients and was not predictive of recurrence. Although postoperative infection did not correlate with the presence of preoperative infection, it was clearly associated with a statistically significant incidence of recurrent disease.

Adolescent↗
PubMed2004

Aberrant fibroblast growth factor receptor 2 signalling in esophageal atresia with tracheoesophageal fistula.

BACKGROUND: Although the pathogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) remains unknown, it has been shown that despite its esophageal appearance, the fistula tract originates from respiratory epithelium. The authors now hypothesize that defects in fibroblast growth factor (FGF) signaling contribute to the esophaguslike phenotype of the fistula tract. FGF2R is critical to normal lung morphogenesis and occurs in 2 isoforms (FGF2RIIIb and FGF2RIIIc), each with different ligand-binding specificity. To characterize FGF signaling in the developing EA/TEF, the authors analyzed levels of FGF2R splice variants in experimental EA/TEF. METHODS: The standard Adriamycin-induced EA/TEF model in rats was used. Individual foregut components from Adriamycin-treated and control embryos were processed for real-time, fluorescence-activated semiquantitative reverse transcriptase polymerase chain reaction on gestational days 12.5 and 13.5. RESULTS: Both fistula tract and Adriamycin-treated or normal esophagus showed significantly lower levels of FGF2RIIIb than either Adriamycin-treated lung buds (E12.5, P =.02; E13.5, P <.005) or normal lung buds (E12.5, P <.005; E13.5, P <.01). At E13.5, the fistula tract had lower levels of FGF2RIIIc than either treated (P <.01) or normal lung (P <.05). CONCLUSIONS: Levels of FGF2R in the developing fistula tract resemble that of distal esophagus rather than developing lung. This defect in FGF2RIIIb signaling may account for the nonbranching, esophaguslike phenotype of the fistula, despite its respiratory origin.

Animals↗
PubMed2004

Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver.

BACKGROUND: Pancreatic duodenal homeobox gene-1 (PDX-1) has a dual task as a key regulator in pancreatic organogenesis and in functional maintenance of beta cells in adults. Recent studies have shown a close lineage relationship between the liver and the pancreas. In this study, we analyzed the plasticity of the liver by enforced expression of PDX-1 in streptozotocin (STZ)-treated mice under the condition of hepatic regeneration. METHODS: Replication-deficient adenoviruses were constructed by the cosmid-adenoviral DNA terminal protein complex method. Mice were treated with STZ (200 mg/kg ip), and a 40% partial hepatectomy was performed at day 0. After 24 hours, Ad-pdx-1 or Ad-lacZ 2.0 x 10(9) PFU/body was injected via the tail vain into nontreated (control), STZ-treated, or STZ plus partial hepatectomy (Hx)-treated ICR mice. After 7 and 14 days, expression of PDX-1 and islet hormones was examined by immunohistologic and reverse transcription-polymerase chain reaction analysis. Blood glucose concentrations were measured every 2 days. Immunoreactive insulin (IRI) of serum and liver extract was measured by ELISA. RESULTS: Most hepatocytes of Ad-pdx-1-infected mice were positive for PDX-1 expression by immunohistochemistry. In nontreated mice, very few cells expressed insulin and other hormones. In contrast, insulin and somatostatin were expressed in STZ-treated mice, and more cells were expressed in STZ plus Hx-treated mice. In addition, other beta-cell markers like GLUT2 and glucokinase were observed. Hyperglycemia was improved in STZ-treated mice and STZ plus Hx-treated mice. IRI of serum and liver extract was increased in STZ-treated mice and STZ plus Hx-treated mice. The insulin positive area of the liver in STZ plus Hx-treated mice was larger than that in nontreated and STZ-treated mice. CONCLUSIONS: Ectopic PDX-1 expression alone may be insufficient to induce insulin-producing cells in the liver. STZ-induced hyperglycemia plus partial hepatectomy that leads to diabetic state and hepatic regeneration may stimulate the transdifferentiation of liver cells into insulin-producing cells.

Adenoviridae↗
PubMed2004

An effective pyloromyotomy length in infants undergoing laparoscopic pyloromyotomy.

BACKGROUND: Traditional management of pyloric stenosis has consisted of open pyloromyotomy during which the surgeon is able to palpate and determine whether the hypertrophied pylorus has been completely divided. During the last decade, laparoscopic pyloromyotomy has become an increasingly popular approach for this condition. The purpose of this study was to determine whether there is an effective pyloromyotomy length that will allow the surgeon to feel confident that a complete pyloromyotomy was performed with the laparoscopic approach. METHODS: All infants undergoing laparoscopic pyloromyotomy from October 1999 through October 2003 at a single institution were retrospectively studied. Clinical variables collected included the patient's age, gender, electrolyte status on admission, the elapsed time from admission to operation, ultrasonographic dimensions of the hypertrophied pylorus, operative time, the length of the pyloromyotomy performed, the time to initial and to full feedings, and the duration of the postoperative hospitalization. RESULTS: One hundred seventy-one patients comprised the study group. The age (mean +/- standard deviation) at the time of operation was 5.2 +/- 2.8 weeks. The mean preoperative ultrasonic measurements for both pyloric thickness and pyloric length were 4.3 +/- 0.7 mm and 19.5 +/- 2.8 mm, respectively. The average pyloromyotomy incision length for this entire group was 1.9 +/- 0.21 cm. The mean operative time was 23.5 +/- 8.3 minutes. There were no mucosal perforations, no conversions to an open procedure, and no evidence for an incomplete pyloromyotomy. CONCLUSIONS: Laparoscopic pyloromyotomy is a safe and effective technique for infants with pyloric stenosis. A pyloromyotomy incision length of approximately 2 cm appears to be an effective measure of a complete pyloromyotomy.

Digestive System Surgical Procedures↗
PubMed2004

Extracellular control of pancreatic differentiation.

Our understanding of basic mechanisms of differentiation has evolved rapidly in the last two decades. Spurred by advances in molecular biology and other research technologies, these advances have become of heightened importance with the recent advent of the possibility of engineering different types of stem cells into needed cell and tissue sources. As pediatric surgeons, we have the potential to play a key role in interfacing between the basic science necessary to understand differentiation processes, and its application at the bedside. In this brief article, we outline our in-depth analysis of mechanisms of basic differentiation of pancreatic precursor cells in an effort to better understand ways in which we can engineer a stem cell pool to form mature pancreatic cells.

Activins↗