Biomedical subjects

Daniel H Teitelbaum

Publications and source records attributed to Daniel H Teitelbaum.

50 records · Page 3Linked to original sources

PubMed2003

Alteration in epithelial permeability and ion transport in a mouse model of total parenteral nutrition.

OBJECTIVE: To investigate the effects of total parenteral nutrition administration on intestinal ion transport and intestinal epithelial permeability. Additionally, to assess the role of interferon-gamma on the total parenteral nutrition-induced loss of epithelial barrier function. DESIGN: Randomized, controlled study. SETTING: Experimental laboratory, University of Michigan Medical School, Ann Arbor. SUBJECTS: Adult wild-type and interferon-gamma knockout mice. INTERVENTIONS: Wild-type mice received total parenteral nutrition or enteral diet (control group) for 7 days. Segments of small bowel from the mice were mounted in Ussing chambers. Short circuit current, as an indictor of active ion transport, was constantly monitored. Epithelial barrier function was assessed by measuring transepithelial resistance and transmural passage of 51Cr-EDTA and 3H-mannitol. Intestinal intraepithelial lymphocyte-derived interferon-gamma protein expression was detected with enzyme-linked immunosorbent assay and confirmed by using intracellular staining and flow cytometry. To investigate the effect of total parenteral nutrition on intestinal ion transport, we used a secretory agonist, carbachol, and an absorptive agent, glucose. MEASUREMENTS AND MAIN RESULTS: Total parenteral nutrition significantly increased small-bowel permeability. Ion transport in the total parenteral nutrition group was significantly increased. To stimulate ion transport, we found that increases in short circuit current induced by carbachol and glucose were higher in the total parenteral nutrition group compared with the control group. Intestinal intraepithelial lymphocyte interferon-gamma protein expression significantly increased with the administration of total parenteral nutrition. Intestinal permeability in interferon-gamma knockout total parenteral nutrition mice was significantly lower than in wild-type mice receiving total parenteral nutrition. CONCLUSION: Total parenteral nutrition has significant effects on intestinal epithelial physiology, stimulating ion secretion and reducing epithelial barrier function. Interferon-gamma appears to play an important role in the loss of the epithelial barrier function that is associated with total parenteral nutrition.

Animals↗

PubMed2003

One-stage transanal Soave pullthrough for Hirschsprung disease: a multicenter experience with 141 children.

BACKGROUND: The surgical management of Hirschsprung's disease (HD) has evolved from the original 3-stage approach to the recent introduction of minimal-access single-stage techniques. We reviewed the early results of the transanal Soave pullthrough from 6 of the original centers to use it. METHODS: The clinical course of all children with HD undergoing a 1-stage transanal Soave pullthrough between 1995 and 2002 were reviewed. Children with a preliminary stoma or total colonic disease were excluded. RESULTS: There were 141 patients. Mean time between diagnosis and surgery was 32 days, and mean age at surgery was 146 days. Sixty-six (47%) underwent surgery in the first month of life. Forty-seven (33%) had the pathologic transition zone documented laparoscopically or through a small umbilical incision before beginning the anal dissection. Mean blood loss was 16 mL, and no patients required transfusion. Mean time to full feeding was 36 hours, mean postoperative hospital stay was 3.4 days, and 87 patients (62%) required only acetaminophen for pain. Early postoperative complications included perianal excoriation (11%), enterocolitis (6%), and stricture (4%). One patient died of congenital cardiac disease. Mean follow-up was 20 months; 81% had normal bowel function for age, 18% had minor problems, and 1% had major problems. Two patients required a second operation (twisted pullthrough, and residual aganglionosis). One patient developed postoperative adhesive bowel obstruction. CONCLUSION: To date, this report represents the largest series of patients undergoing the 1-stage transanal Soave pullthrough. This approach is safe, permits early feeding, causes minimal pain, facilitates early discharge, and presents a low rate of complications.

Child↗

PubMed2002

Growth factor stimulation of matrix metalloproteinase expression and myoblast migration and invasion in vitro.

We investigated the role of growth factors and fibronectin on matrix metalloproteinase (MMP) expression and on migration and invasion of mouse skeletal myoblasts in vitro. None of the growth factors tested significantly affected MMP-1 or MMP-2 activity as revealed by gelatin zymography, but both basic FGF (bFGF) and tumor necrosis factor (TNF)-alpha significantly increased MMP-9 activity (10- and 30-fold, respectively). The increase in secreted MMP-9 activity with TNF-alpha stimulation was due at least in part to an increase in MMP-9 gene transcription, because an MMP-9 promoter construct was approximately fivefold more active in TNF-alpha-treated myoblasts than in control myoblasts, as well as an increase in MMP-9 proteolytic activation. However, whereas fibronectin, bFGF, hepatocyte growth factor, and TGF-beta1 significantly augmented migration of mouse myoblasts, TNF-alpha did not, nor did PDGF-BB or IGF-I. Fibronectin and bFGF also significantly augmented invasion of myoblasts across a Matrigel barrier, and plasmin cotreatment potentiated whereas N-acetyl cysteine suppressed the effects of bFGF and fibronectin on myoblast migration and invasion. Finally, transient transfection with an MMP-9 overexpression construct had only minimal effects on myoblast migration/invasion, whereas overexpression of either MMP-2 or MMP-1 significantly augmented myoblast migration and invasion. These observations support the hypothesis that MMP activity is a necessary component of growth factor-mediated myoblast migration but suggest that other consequences of growth factor signaling are also necessary for migration to occur.

Animals↗

PubMed2002

Probiotics up-regulate MUC-2 mucin gene expression in a Caco-2 cell-culture model.

Enteral probiotics such as Lactobacillus casei GG (LGG) have been used in the treatment of a variety of intestinal disorders in infants and children, including diarrhea, malabsorption, and Clostridium difficile colitis. Previous studies have identified the gene locus for mucin (MUC-2) and its expression in Caco-2 cells. Others have demonstrated that mucin, located on the surface of the intestinal epithelium, inhibits bacterial translocation (BT). We previously demonstrated that both mucin and the probiotic bacterium LGG have an inhibitory effect on BT in both an in-vitro Caco-2 cell model and a neonatal rabbit model. We hypothesized that the decline in BT by LGG is mediated by up-regulation of epithelial MUC-2. Human enterocyte Caco-2 cells were grown to confluence and incubated at 37 degrees C with either medium (control group) or 10(4) or 10(8) LGG for 180 min. Non-adherent LGG was washed away. Caco-2 cells were then lysed, purified, and quantified for MUC-2 protein and mRNA. The addition of LGG to the enterocyte monolayer surface resulted in significantly ( P < 0.05) increased MUC-2 expression compared to the untreated monolayers. Protein densities for MUC-2 significantly ( P < 0.05) increased with LGG. Density (expressed as ratio to control group) was 8.6 +/- 1.3 in the low-dose group (10(4) LGG) and 15.6 +/- 2.3 in the high-dose group (10(8) LGG). LGG may thus bind to specific receptor sites on the enterocyte and stimulate the up-regulation of MUC-2, resulting in increased inhibition of BT.

Animals↗

PubMed2002

Total parenteral nutrition-associated changes in mouse intestinal intraepithelial lymphocytes.

Intraepithelial lymphocytes (IEL) play a major role in mucosal defense mechanisms against intraluminal foreign antigens. To address the role luminal nutrients have on the phenotype and function of the IEL, we administered total parenteral nutrition (TPN) to mice, with the absence of enteral intake. We hypothesized that administration of TPN would result in changes in the phenotype and function of the IEL. For this, we utilized a mouse model of TPN. A significant decline in the CD4+ IEL population occurred with TPN. Additionally, the CD8+,CD44+ IEL subset showed a 65% decline (P < 0.05), and the CD4+,CD44+ subset declined by 55% with TPN (P < 0.05). The CD8alphabeta+ population (a marker of thymic-dependence) also declined by 92% (P < 0.01) with TPN. IEL in the TPN group showed a significantly lower degree of in vitro proliferation. In conclusion, the IEL showed significant phenotypic changes with TPN including the loss of the thymic-derived population. Functionally, the IEL showed a significant decline in proliferation. Such changes demonstrate the important role luminal nutrients have on IEL phenotype and function.

Animals↗

PubMed2002

Vaginal reconstruction for ambiguous genitalia and congenital absence of the vagina: a 27-year experience.

BACKGROUND/PURPOSE: Gender assignment to a neonate with ambiguous genitalia is crucial. Patients with an absent vagina require the construction of an artificial vagina. In an effort to improve care, the authors have categorized their experience with this group of children. METHODS: Since 1974, we cared for 114 patients with anomalies of the genitalia. There were 53 genotypic girls with congenital adrenal hyperplasia (CAH), 16 genotypic boys with testicular feminization syndrome (TFS), 13 with mixed gonadal dysgenesis (MGD), 9 with Mayer-Rokitansky syndrome, and 4 true hermaphrodites. The remaining 19 had other genital abnormalities. RESULTS: After 1980, patients with CAH underwent clitoral recession and vaginoplasty. All patients with TFS were raised as girls and underwent orchidectomy. Eleven of the MGD patients were given a female sex assignment and underwent gonadectomy. Twenty-eight patients underwent intestinal vaginoplasty including 8 of the TFS patients, 9 with Mayer-Rokitansky syndrome, 8 patients with cloacal anomalies, 2 patients for rhabdomyosarcoma, and 1 of the MGD patients. CONCLUSIONS: (1) This review emphasizes the range of diagnoses the surgeon must be prepared to address in patients with ambiguous genitalia. (2) Colovaginoplasty is an excellent procedure for replacement of a completely absent vagina. (3) Continued evaluation of this group will delineate appropriate timing and choice of procedure.

Adolescent↗

PubMed2002

Successful thoracoscopic lung biopsy in children utilizing preoperative CT-guided localization.

BACKGROUND/PURPOSE: Although thoracoscopy in children is a well-accepted technique, there are limitations to this approach. Small lung nodules or those not located on the pleural surface often require an open thoracotomy. The purpose of this report is to evaluate the utility of computed tomography (CT) guided needle localization of lung nodules in children followed by thoracoscopic resection. METHODS: From 1997 to 2000, 13 thoracoscopic procedures were performed on 12 children who presented with small pulmonary nodules (<1 cm) or nodules deep to the pleural surface. Preoperative needle localization was performed by injecting methylene blue under CT guidance. Patients then were taken directly to the operating room for thoracoscopic resection. RESULTS: All 13 procedures were completed successfully thoracoscopically. Twelve yielded diagnostic pathologic findings as well as therapeutic resections in 7. All patients underwent extubation in the operating room, and chest tubes were removed within 36 hours. No thoracotomies were performed, and there were no complications. CONCLUSIONS: Preoperative localization utilizing CT guidance is safe and beneficial in children with pulmonary nodules less than 1 cm in size and those located deep to the pleural surface. This technique allows the surgeon to perform thoracoscopy for diagnosis and therapeutic resection of these lesions rather than submitting patients to the morbidity of a thoracotomy.

Adolescent↗

PubMed2002

Stooling and manometric findings after primary pull-throughs in Hirschsprung's disease: Perineal versus abdominal approaches.

BACKGROUND/PURPOSE: Primary pull-through via a perineal approach (PA) has recently been reported for Hirschsprung's disease. One criticism of this approach is that it requires a large amount of retraction on the anal sphincters. Additionally, because the procedure is new, most patients undergoing a PA are too young to assess long-term continence rates. This study examined early stooling patterns, anal sphincteric pressures, and number of enterocolitic episodes in infants who underwent a PA. Results were compared with a conventional combined transabdominal and perineal approach (TA). METHODS: Over 2 years, 26 pull-through procedures were performed. Nine of those were PA, and 17 were TA. Twelve of the 26 patients had formal manometric studies postoperatively. Results are expressed as mean +/- SD; unpaired t test and Chi;(2) were used for statistical analysis. RESULTS: Mean follow-up post-pull-through was 23 +/- 2.3 months for the TA and 14 +/- 1.9 months for the PA. Manometric resting sphincter pressure in the TA group averaged 79 +/- 17 mm Hg compared with 76 +/- 21 mm Hg in the PA group (P =.78). Number of stools per day was 3.3 +/- 0.6 in the TA group compared with 2.2 +/- 0.3 in the PA group (P =.17). Post-pull-through enterocolitis was experienced by 53% of the TA group (mean, 1.5 +/- 0.6 episodes) and 56% of the PA group (mean 0.9 +/- 0.4 episodes) for a P =.08 by Chi;(2) analysis. CONCLUSIONS: Manometric sphincter pressure and enterocolitic episodes after a PA for Hirschsprung's disease appear to be similar to results obtained with a conventional TA. Evaluation of early stooling frequency shows a comparable frequency after a PA. This suggests that both methods are safe, and the PA does not appear to compromise sphincter integrity.

Anal Canal↗

PubMed2002

Interferon-gamma expression by intraepithelial lymphocytes results in a loss of epithelial barrier function in a mouse model of total parenteral nutrition.

OBJECTIVE: To determine the etiology of the loss of epithelial barrier function observed with the administration of total parenteral nutrition (TPN) in a mouse model. SUMMARY BACKGROUND DATA: Removal of enteral nutrition with the administration of TPN is associated with a loss of intestinal epithelial barrier function. The etiology of this barrier loss is not clear. Because intraepithelial lymphocytes (IELs) produce a number of cytokines that may alter epithelial permeability, the authors investigated IEL cytokine expression in a mouse model of TPN. METHODS: Adult C57BL/6 mice received TPN or enteral diet for 7 days. IELs were subsequently harvested and the mRNA expression of cytokines was measured. Epithelial barrier function was assessed in vitro with 51Cr-EDTA in Ussing chambers and was expressed as the permeability coefficient (Papp). RESULTS: IEL mRNA expression of interferon-gamma (IFN-gamma) rose from 0.14 +/- 0.07 in the control (enterally fed) group to 0.44 +/- 0.11 attomoles/microL in the TPN group (P <.05). Transforming growth factor-beta1 declined slightly but not significantly, from 0.75 +/- 0.35 to 0.55 +/- 0.18 attomoles/microL in the control and TPN groups, respectively. Epithelial barrier function declined significantly with TPN compared to controls. To assess the relevance of IFN-gamma changes, permeability in IFN-gamma knockout mice was studied. Barrier function was significantly higher in IFN-gamma knockout mice on TPN compared to C57BL/6 mice that received TPN. CONCLUSIONS: IEL cytokine expression changes significantly with TPN administration. The partial correction with IFN-gamma knockout mice suggests that an upregulation of IFN-gamma expression is one mechanism responsible for the loss of the epithelial barrier associated with TPN.

Animals↗

PubMedDate not supplied

2002 Harry M. Vars Research Award. Keratinocyte growth factor stimulates the recovery of epithelial structure and function in a mouse model of total parenteral nutrition.

BACKGROUND: Keratinocyte growth factor (KGF) increases intestinal growth and is expressed by intestinal intraepithelial lymphocytes (IEL). Because total parenteral nutrition (TPN) leads to villus atrophy and a loss of epithelial function, we hypothesized that KGF administration could reverse these changes. METHODS: Mice were randomized into three groups: oral feeding (Control); TPN; or TPN with recombinant human KGF. Mice were killed at 7 days, and the small bowel was harvested for histology, DNA, and protein content analysis. Epithelial cell proliferation was studied by 5-bromo-2-deoxyuridine (BrdU) incorporation, and apoptosis was detected by flow cytometry with Annexin V staining. Epithelial ion transport function was studied by Ussing chambers. Epithelial barrier function was assessed with transepithelial resistance and transmural passage of 3H-mannitol. Epithelial KGF receptors expression was studied by using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: TPN decreased intestinal DNA, protein content, villus height, and crypt cell proliferation. TPN also resulted in an increase in epithelial cell apoptosis. KGF administration significantly stimulated the recovery of mucosal structures including intestinal protein and DNA content, villus height, and crypt cell proliferation, and decreased epithelial apoptosis. KGF also up-regulate the epithelial KGF receptor expression. Moreover, KGF attenuated the TPN-induced increase in ion transport and increased the epithelial barrier function. CONCLUSIONS: KGF administration reversed many of the adverse epithelial changes associated with TPN administration. Additionally, KGF up-regulated epithelial KGF receptor expression. It is possible that KGF may have a therapeutic efficacy in patients who are receiving TPN.

Animals↗

PubMedDate not supplied

2003 Harry M. Vars Research Award. Keratinocyte growth factor improves epithelial function after massive small bowel resection.

BACKGROUND: Massive small bowel resection with subsequent short bowel syndrome (SBS) leads to the acute loss of epithelial cell (EC) absorptive function. Keratinocyte growth factor (KGF) has been shown to improve EC growth, although little is known about KGF activity on EC function after SBS. We hypothesized that KGF would improve epithelial function in a mouse SBS model. METHODS: Adult C57BL/6J mice were randomized to a 55% mid-small bowel resection (SBS), SBS with KGF administration (SBSKGF), or sham-operated (Control) group, and were killed at 7 days. Ussing chambers were used to study epithelial function. Short circuit current (Isc) was monitored. EC absorption was studied by measuring (1) glucose [3-O-methyl-D-[1-3H]glucose (3-OMG)] absorption; (2) sodium coupled amino acid (alanine) absorption; and (3) changes in Isc by using the absorptive agent D-glucose (stimulated Na+ absorption). Epithelial barrier function was measured with transepithelial resistance (TER) and transmural passage of 3H-mannitol (Papp). ECs were separated along the crypt-villus axis with laser capture microdissection. Epithelial KGF receptor (KGFR) mRNA expression was studied using real time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: KGF administration increased the basic ion transport activity and net transepithelial absorption of 3-OMG and sodium-coupled alanine absorption. SBS significantly decreased epithelial ion transport, including the Na+ absorption stimulated by D-glucose and L-alanine. KGF administration partially improves Na+ absorption. KGF had no apparent effect on the TER and 3H-mannitol permeability in this study. KGF upregulated EC KGFR mRNA expression, predominately in the crypt and lower portion of the villus. CONCLUSIONS: KGF administration improves epithelial absorptive function and stimulates intestinal proliferation after SBS. This suggests that KGF improves intestinal adaptation after SBS and may have clinical applicability.

Animals↗

PubMedDate not supplied

Hepatic P-glycoprotein changes with total parenteral nutrition administration.

BACKGROUND: The mechanism(s) responsible for the development of parenteral nutrition-associated liver disease (PNALD) is unknown. Recently, a number of bile canalicular transport proteins have been identified that transport bile components out of hepatocytes. One group of these genes, multidrug resistance 1 (mdr1) and mdr2, encode P-glycoproteins. Mice lacking mdr2 expression develop liver disease that appears similar to PNALD. This study investigated the alteration in the expression of these transport proteins during the administration of total parenteral nutrition (TPN). METHODS: Mice received either physiologic saline and standard chow or TPN. Mice were sacrificed on day 7, and hepatic DNA and RNA content, mRNA expression, and levels of mdr1 and mdr2 proteins were measured. RESULTS: TPN administration led to a significant (p < .05) decline in mdr2 mRNA expression and an increase in mdr1 mRNA expression. Mdr2 protein expression declined by 66% in the TPN-treated group, and mdr1 protein expression significantly increased by 58%. Histology and biochemical parameters showed no evidence of liver injury. Serum bile acid levels were elevated in the TPN group, suggesting the development of early cholestasis. CONCLUSIONS: The decline in mdr2 and rise in mdr1 mRNA and protein expression with TPN administration occurred before the development of liver injury but during an early state of cholestasis. This suggests that alterations in mdr gene expression may be a causative factor in the development of PNALD.

ATP Binding Cassette Transporter, Subfamily B↗

PubMedDate not supplied

Parenteral nutrition-associated cholestasis in neonates: multivariate analysis of the potential protective effect of taurine.

BACKGROUND: Neonates receiving parenteral nutrition (PN) are at risk for PN-associated cholestasis (PNAC); however, no preventive factors for PNAC have been clearly identified. Despite reports suggesting that taurine may prevent PNAC in neonates, such an effect of taurine has not yet been definitively demonstrated. We determined whether taurine supplementation reduces the incidence of PNAC in premature or critically ill neonates. METHODS: This study was part of a prospective, randomized, multi-institutional trial designed to assess cholecystokinin vs placebo as a potential preventive therapy of PNAC. Taurine supplementation of PN varied between institutions. The presence or absence of taurine in PN was analyzed by multivariate analysis, with a primary outcome measure of serum conjugated bilirubin (CB) as a measure of PNAC. RESULTS: Taurine reduced PNAC in premature infants (estimated maximum CB [95% confidence interval] 0.50 mg/dL [-0.17 to 1.18] for those receiving taurine, vs 3.45 mg/dL [1.79-5.11] for neonates not receiving taurine, approaching significance, p = .07). Taurine significantly reduced PNAC in infants with necrotizing enterocolitis (NEC; estimated maximum CB 4.04 mg/dL [2.85-5.23], NEC infants receiving taurine, vs 8.29 mg/dL [5.61-10.96], NEC infants not receiving taurine, p < .01). There were too few neonates with surgical anomalies to evaluate the effect of taurine in this group. CONCLUSIONS: Within specific subgroups of neonatal patients, taurine supplementation does offer a very significant degree of protection against PNAC. Patients with NEC or severe prematurity are most likely to benefit substantially from taurine supplementation.

Bilirubin↗

PubMedDate not supplied

Impact of caloric intake on parenteral nutrition-associated intestinal morphology and mucosal barrier function.

BACKGROUND: Parenteral nutrition (PN) is known to induce villus atrophy, epithelial cell (EC) apoptosis, and increase mucosal permeability. The study hypothesized that increasing amounts of energy delivery to mice would result in the best outcome, with the least effects on the mucosa. METHODS: Mice were randomized to enteral controls (saline infusion with ad libitum enteral food) or to 1 of 3 PN groups (with no enteral nutrition): full (100% of daily average energy intake for the mouse), reduced (75% of energy intake) or very low (50% of energy intake). Mice received PN for 7 days. Mucosal morphology, EC apoptosis, and bacterial translocation were assessed. RESULTS: Villus height decreased significantly with decreasing levels of caloric intake and was significantly lower in all PN groups compared with controls. Body weight loss was significantly greater in PN groups vs controls and was greatest in mice with the lowest caloric delivery. A consistent trend toward a higher EC apoptotic index with decreasing caloric intake was observed, and apoptosis in all PN groups exceeded controls (2-fold). All PN groups demonstrated greater bacterial translocation than controls. CONCLUSIONS: PN induces intestinal EC apoptosis and villus and crypt atrophy, even at 100% of predicted energy needs, and such changes increased with greater reduction of energy intake. This study supports a concept that lack of enteral nutrition, rather than absolute caloric levels, is responsible for many of the adverse effects of PN. The study also allows the investigators to better optimize a mouse model of PN delivery.

Animals↗