Routine prophylactic central neck dissection for low-risk papillary thyroid cancer is not cost-effective.

BACKGROUND: The role of routine prophylactic central neck dissection (CND) in papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the cost utility of the addition of routine CND in patients with low-risk PTC compared with total thyroidectomy (TT) alone. METHODS: A Markov model for low-risk PTC was constructed with a treatment algorithm based on the American Thyroid Association guidelines for well-differentiated thyroid carcinoma. Utilities and outcome probabilities were derived from published medical literature. US 2010 costs were examined from a society perspective using Medicare reimbursement rates and opportunity loss based on published US government data. Monte Carlo simulation and sensitivity analysis were used to examine the uncertainty of probability, cost and utility estimates. RESULTS: Initial TT alone is more cost-effective than TT with CND, resulting in a cost savings of US $5763 per patient with slightly higher effectiveness per patient (0·03 QALY) for a cost savings of $285 per QALY. Sensitivity analysis shows that TT alone offers no advantage when radioactive iodine (RAI) becomes more detrimental to a patient's state of health, when the incidence of non-neck recurrence increases above 5% in patients undergoing TT alone or decreases below 3·9% in patients undergoing TT with CND or when the rate of permanent hypocalcaemia rises above 4%. CONCLUSIONS: TT with CND is not a cost-effective strategy in low-risk PTC. Initial TT alone is favourable because of the low complication rates and low recurrence rates associated with the initial surgery. Alternative strategies such as unilateral prophylactic neck dissection require additional study to assess their cost-effectiveness.

Ontogenesis of taurocholate transport by rat ileal brush border membrane vesicles.

Developmental aspects of taurocholate transport into ileal brush border membrane vesicles were studied in 2-wk-old (suckling), 3-wk-old (weanling), and 6-wk-old (adolescent) rats. Taurocholate uptake (picomoles per milligram protein) into brush border membrane vesicles prepared from 2-wk-old rats was similar under Na+ and K+ gradient conditions (outside greater than inside). By contrast, uptake in 3- and 6-wk-old rats was significantly enhanced at 20 s, and at 1, 2, and 5 min of incubation in the presence of a Na+ gradient when compared with a K+ gradient incubation (P less than 0.05). Under isotope exchange conditions, a plot of active uptake velocity versus taurocholate concentration (0.10-1.0 mM) in 2-wk-old rat membrane vesicles was linear and approached the horizontal axis, suggesting the absence of active transport. However, similar plots in 3- and 6-wk-old rats described a rectangular hyperbola, indicating a Na+-dependent, saturable cotransport system. Woolf-Augustinsson-Hofstee plots of the uptake velocity versus concentration data from 3- and 6-wk-old rat brush border membrane vesicles yielded Vmax values that were not significantly different, 844 and 884 pmol uptake/mg protein per 120 s, respectively. The respective Km values were 0.59 and 0.66 mM taurocholate. The induction of an electrochemical diffusion potential by incubating K+-loaded vesicles with valinomycin did not significantly enhance taurocholate uptake in 2-, 3-, or 6-wk-old rat vesicle preparations. These data indicate that taurocholate transport into rat ileal brush border membrane vesicles is mediated by an electroneutral, sodium-coupled, cotransport system that is incompletely developed in the 2-wk-old suckling rat but fully developed by the time of weaning at 3 wk of age.

Localization of transforming growth factor alpha and its receptor in gastric mucosal cells. Implications for a regulatory role in acid secretion and mucosal renewal.

Transforming growth factor alpha (TGF alpha) shares with epidermal growth factor (EGF) structural homology (35%), a common cell-surface membrane receptor (TGF alpha/EGF receptor), and a nearly identical spectrum of biological activity, including inhibition of gastric acid secretion. Herein, we report expression of TGF alpha mRNA in normal gastric mucosa of the adult guinea pig, rat, and dog. TGF alpha mRNA was also detected in matched surgically resected gastric mucosa and adjacent gastric carcinoma from 10 patients, and in gastric mucosa adjacent to a benign ulcer from an additional patient. TGF alpha protein was quantitated by radioimmunoassay and was present in tumor and adjacent mucosa. TGF alpha/EGF receptor mRNA was also detected in gastric mucosa from all species studied. Localization of TGF alpha and TGF alpha/EGF receptor mRNA expression was examined in samples of unfractionated guinea pig gastric mucosa and from chief cell-enriched and parietal cell-enriched fractions. All samples exhibited TGF alpha and TGF alpha/EGF receptor expression. The TGF alpha signal was greatest in the parietal cell fraction (5.8-fold increase), but was also enhanced in the chief cell fraction (1.9-fold increase) relative to the unfractionated gastric mucosa. Like TGF alpha expression, TGF alpha/EGF receptor mRNA expression was most intense in the parietal cell-enriched fraction (7.8-fold increase), but was also increased in the chief cell-enriched fraction (2.7-fold increase) relative to the unfractionated guinea pig gastric mucosa. We conclude that TGF alpha and TGF alpha/EGF receptor genes are expressed in normal adult mammalian gastric mucosa. These findings, when interpreted in light of described actions of TGF alpha and EGF, provide evidence that local production of TGF alpha could play an important role in the regulation of acid secretion and mucosal renewal in the stomach.

Differential trafficking of transforming growth factor-beta receptors and ligand in polarized epithelial cells.

Epithelial cells in vivo form tight cell-cell associations that spatially separate distinct apical and basolateral domains. These domains provide discrete cellular processes essential for proper tissue and organ development. Using confocal imaging and selective plasma membrane domain activation, the type I and type II transforming growth factor-beta (TGFbeta) receptors were found to be localized specifically at the basolateral surfaces of polarized Madin-Darby canine kidney (MDCK) cells. Receptors concentrated predominantly at the lateral sites of cell-cell contact, adjacent to the gap junctional complex. Cytoplasmic domain truncations for each receptor resulted in the loss of specific lateral domain targeting and dispersion to both the apical and basal domains. Whereas receptors concentrate basolaterally in regions of direct cell-cell contact in nonpolarized MDCK cell monolayers, receptor staining was absent from areas of noncell contact. In contrast to the defined basolateral polarity observed for the TGFbeta receptor complex, TGFbeta ligand secretion was found to be from the apical surfaces. Confocal imaging of MDCK cells with an antibody to TGFbeta1 confirmed a predominant apical localization, with a stark absence at the basal membrane. These findings indicate that cell adhesion regulates the localization of TGFbeta receptors in polarized epithelial cultures and that the response to TGFbeta is dependent upon the spatial distribution and secretion of TGFbeta receptors and ligand, respectively.

Peer video review and feedback improve performance in basic surgical skills.

BACKGROUND: Incorporation of home-video assessments allows flexibility in feedback but requires faculty time. Peer feedback (PF) may provide additional benefits while avoiding these constraints. METHODS: Twenty-four surgical interns completed a 12-week skills curriculum with home-video assignments focused on knot tying and suturing. Interns were randomized into 2 groups: PF or faculty feedback (FF). Peers and faculty provided feedback on home videos with checklists, global rating, and comments. Learners' skills were assessed at baseline, during, and at the conclusion of the curriculum. Performance of the 2 groups as rated by experts was compared. FF and PF were compared. RESULTS: Both groups improved from baseline, and the highest rated scores were seen on their home-video assessments. The PF group performed better at the final assessment than the FF group (effect size, .84). When using a checklist, there was no significant difference between scores given by peers and faculty. CONCLUSIONS: The PF group performed better at the final assessment, suggesting reviewing and analyzing another's performance may improve one's own performance. With checklists as guidance, peers can serve as raters comparable to faculty.

The cell biology of transforming growth factor beta.

The TGF beta family of polypeptide growth factors regulates a remarkable diversity of cellular functions, many of which are not directly associated with cell growth. The present review has summarized many of the recent studies that have just begun to conceptually integrate this expanding array of TGF beta functions into the context of a three-dimensional, multicellular organ or tissue, be it normal or diseased. This fascinating research strongly implicates TGF beta as a key modulator of a wide variety of important physiologic and pathophysiologic processes.

Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling.

Ras-transformed intestinal epithelial cells are resistant to the growth inhibitory actions of TGFbeta and have a marked decrease in expression of the TGFbeta type II receptor (TGFbetaRII). Rat intestinal epithelial cells (RIE) were stably transfected with activated Ras, Sos and Raf constructs and tested for expression of TGFbetaRII and sensitivity to growth inhibition by TGFbeta. The parental RIE line and the RIE-Raf cells were non-transformed in morphology and were sensitive to TGFbeta (70-90% inhibited). In contrast, the RIE-Ras and RIE-Sos lines were transformed, resistant to TGFbeta and expressed 5- to 10-fold decreased levels of the TGFbetaRII mRNA and protein. Cyclin D1 protein expression was repressed by TGFbeta treatment in parental RIE and RIE-Raf cells, whereas levels of cyclin D1 in RIE-Ras and RIE-Sos cells remained unchanged. Treatment of RIE-Ras cells with 25 microM farnesyl transferase inhibitor, FTI L739,749, for 48 hours restored expression of TGFbetaRII to levels equivalent to control cells. In addition, treatment of RIE-Ras cells for 48 hours with PD-98059, a specific MAPKK inhibitor, also increased expression of TGFbetaRII to control levels. Collectively these results suggest that downregulation of TGFbetaRII and loss of sensitivity to growth inhibition by TGFbeta in Ras-transformed intestinal epithelial cells is not mediated exclusively by the conventional Ras/Raf/MAPKK/MAPK pathway. However, activation of MAPK, perhaps by an alternate Ras effector pathway, appears to be necessary for Ras-mediated downregulation of TGFbetaRII.

Increased intestinal epithelial proliferation in metallothioneine-transforming growth factor alpha transgenic mice.

BACKGROUND AND AIM: The epidermal growth factor (EGF) peptide family includes six closely-related proteins, all of which bind to the EGF receptor. In the intestinal epithelium, transforming growth factor alpha (TGFalpha) appears to be the most physiological ligand for the EGF receptor. The present studies were designed to examine the effect of TGFalpha overexpression on duodenal epithelial proliferation using a metallothioneine-inducible promoter/enhancer transgenic mouse (MT-TGFalpha). The MT-TGFalpha mouse model was further studied to determine the in vivo effect of unregulated TGFalpha production on the physiological proliferative responses to fasting and refeeding. METHODS: MT-TGFalpha mice were given 25 mM oral ZnSO4 to induce transgene expression and were studied 1 to 2 months later. Duodenal histology was analyzed morphometrically in well-oriented transverse sections. The vincristine metaphase-arrest technique was used to assess proliferation in duodenal crypts. Immunohistochemical staining and in situ hybridization were used to assess transgenic TGFalpha protein and mRNA expression, respectively. RESULTS: Normally fed MT-TGFalpha mice had deeper crypts (0.12 vs. 0.08 mm), longer villi (0.66 vs. 0.54 mm), and greater luminal diameters (2.65 vs. 2.19 mm) compared to controls (P<0.05 for all three dimensions). The crypt cell mitotic index in normally fed transgenic mice was 1.5 fold greater than the index in normally fed controls (20+/-2 vs. 35+/-4 mitoses per crypt; P <0.05). Fasting and refeeding MT-TGFalpha mice resulted in no significant change in their high baseline rate of crypt proliferation, while proliferation in control mice rose from a lower baseline during fasting to a level with refeeding that approximated rates in MT-TGFalpha mice. Transgenic TGFalpha protein and mRNA were localized to the villus epithelial compartment with little or no evidence of mRNA or protein expression in the crypt epithelium. CONCLUSION: Overproduction of TGFalpha in the mouse duodenal epithelium results in a pronounced increase in crypt epithelial cell proliferation and a resulting increase in the dimension of the crypt/villus unit. This appears to be mediated through a paracrine and/or juxtacrine effect on crypt cells by TGFalpha produced in the villus epithelium. Fasting and refeeding experiments suggest that TGFalpha may also play a role in the proliferative response to refeeding or that the full potential for proliferation is realized by TGFalpha overexpression alone. Collectively, these studies suggest that TGFalpha is a physiological autocrine and paracrine regulator of small intestinal epithelial proliferation.

Relationship of high energy expenditure and variation in dietary intake with reporting accuracy on 7 day food records and diet histories in a group of healthy adult volunteers.

OBJECTIVES: To assess the accuracy of reporting from both a diet history and food record and identify some of the characteristics of more accurate reporters in a group of healthy adult volunteers for an energy balance study. DESIGN: Prospective measurements in free-living people. SETTING: Wollongong, Australia. SUBJECTS: Fifteen healthy volunteers (seven male, eight female; aged 22-59 y; body mass index (BMI) 19-33 kg/m(2)) from the local community in the city of Wollongong, Australia. INTERVENTIONS: Measurement of energy intake via diet history interview and 7 day food records, total energy expenditure by the doubly labelled water technique over 14 days, physical activity by questionnaire, and body fat by dual-energy X-ray absorptiometry. RESULTS: Increased misreporting of energy intake was associated with increased energy expenditure (r=0.90, P<0.0001, diet history; r(S)=0.79, P=0.0005, food records) but was not associated with age, sex, BMI or body fat. Range in number of recorded dinner foods correlated positively with energy expenditure (r(S)=0.63, P=0.01) and degree of misreporting (r(S)=0.71, P=0.003, diet history; r(S)=0.63, P=0.01, food records). Variation in energy intake at dinner and over the whole day identified by the food records correlated positively with energy expenditure (r=0.58, P=0.02) and misreporting on the diet history (r=0.62, P=0.01). CONCLUSIONS: Subjects who are highly active or who have variable dietary and exercise behaviour may be less accurate in reporting dietary intake. Our findings indicate that it may be necessary to screen for these characteristics in studies where accuracy of reporting at an individual level is critical.

Transforming growth factor beta in the control of epidermal proliferation.

Transforming growth factor beta is a polypeptide growth factor with a multiplicity of diverse biologic effects. Increasingly, data support a role for TGF beta in the autocrine regulation of normal epithelial cell growth (Figure 1). Definition of the normal pathways for growth stimulation and inhibition of epithelial cell growth by autocrine peptides like TGF beta and TGF alpha undoubtedly will increase understanding of normal growth and development, embryogenesis, wound repair, and tumorigenesis.

BRAF mutation in papillary thyroid cancer: A cost-utility analysis of preoperative testing.

BACKGROUND: Papillary thyroid carcinoma (PTC) with BRAF mutation carries a poorer prognosis. Prophylactic central neck dissection (CND) reduces locoregional recurrences, and we hypothesize that initial total thyroidectomy (TT) with CND in patients with BRAF-mutated PTC is cost effective. METHODS: This cost-utility analysis is based on a hypothetical cohort of 40-year-old women with small PTC [2 cm, confined to the thyroid, node(-)]. We compared preoperative BRAF testing and TT+CND if BRAF-mutated or TT alone if BRAF-wild type, versus no testing with TT. This analysis took into account treatment costs and opportunity losses. Key variables were subjected to sensitivity analysis. RESULTS: Both approaches produced comparable outcomes, with costs of not testing being lower (-$801.51/patient). Preoperative BRAF testing carried an excess expense of $33.96 per quality-adjusted life-year per patient. Sensitivity analyses revealed that when BRAF positivity in the testing population decreases to 30%, or if the overall noncervical recurrence in the population increases above 11.9%, preoperative BRAF testing becomes the more cost-effective strategy. CONCLUSION: Outcomes with or without preoperative BRAF testing are comparable, with no testing being the slightly more cost-effective strategy. Although preoperative BRAF testing helps to identify patients with higher recurrence rates, implementing a more aggressive initial operation does not seem to offer a cost advantage.

Pan computed tomography versus selective computed tomography in stable, young adults after blunt trauma with moderate mechanism: a cost-utility analysis.

BACKGROUND: Pan computed tomography (PCT) of the head, cervical spine, chest, abdomen, and pelvis is a valuable approach for rapid evaluation of severely injured blunt trauma patients. A PCT strategy has also been applied for the evaluation of patients with lower injury severity; however, the cost-utility of this approach is undetermined. The advantage of rapidly identifying all injuries via PCT must be weighed against the risk of radiation-induced cancer (RIC). Our objective was to compare the cost-utility of PCT with selective computed tomography (SCT) in the management of blunt trauma patients with low injury severity. METHODS: A Markov model-based, cost-utility analysis of a hypothetical cohort of hemodynamically stable, 30-year-old males evaluated in a trauma center after motor vehicle crash was used. CT scans are performed based on the mechanism of injury. The analysis compared PCT with SCT over a 1-year time frame with an analytic horizon over the lifespan of the patients. The possible outcomes, utilities of health states, and health care costs including RIC were derived from the published medical literature and public data. Costs were measured in US 2010 dollars, and incremental effectiveness was measured in quality-adjusted life-years (QALYs) with 3% annual discounted rates. Multiway sensitivity analyses were performed on all variables. RESULTS: The total cost for blunt trauma patients undergoing PCT was $15,682 versus $17,673 for SCT. There was no difference in QALYs between the two populations (26.42 vs. 26.40). However, there was a cost savings of $75 per QALY for patients receiving PCT versus SCT ($594 per QALY vs. $669 per QALY). CONCLUSION: PCT enables surgeons to identify and rule out injuries promptly, thereby reducing the need for inpatient observation. The risk of RIC is low following a single PCT. This cost-utility analysis finds PCT based on mechanism to be a cost-effective use of resources. LEVEL OF EVIDENCE: Economic and value-based evaluations, level II.

Idiopathic neonatal iron-storage disease.

A 21-day-old infant presented with anemia, conjugated hyperbilirubinemia, hypoproteinemia, and a severe coagulopathy. The hospital course was marked by progressive hepatic failure, encephalopathy, and renal insufficiency. The infant died on day 15 of hospitalization. Postmortem examination showed diffuse hepatic fibrosis and marked siderosis of the liver, pancreas, kidney, adrenal glands, and the duodenal epithelium, with sparing of the reticuloendothelial system. These findings were characteristic of idiopathic neonatal iron-storage disease. Previously reported cases are summarized and discussed. An increased awareness and understanding of this rapidly fatal disorder will be important for genetic counseling and possibly in defining an aberrant mechanism in the handling of iron.

Taurocholate transport by human ileal brush border membrane vesicles.

Human ileal brush border membrane vesicles were prepared from intestines obtained from cadaveric renal allograft donors. The energetics and kinetics of taurocholate transport were studied. Fifty-five percent of equilibrium uptake (picomoles per mg protein) resulted from binding to the vesicle surface or incorporation into an osmotically insensitive compartment. The initial rate of transport was stimulated fourfold by an inwardly directed Na+ gradient when compared with a K+ gradient, and cation gradient-dependent differences persisted throughout the initial 5 min of incubation (p less than 0.05). Taurocholate uptake was half-maximally stimulated by a Na+ concentration of 23 +/- 4 mM. A Hill transformation of this plot gave a slope (n) of 0.97, indicating a 1:1 (mol/mol) Na+-taurocholate coupling ratio. Generation of a negative inside diffusion potential by anion substitution or valinomycin-induced K+ diffusion potential failed to alter bile salt uptake, suggesting an electroneutral transport mechanism. When Na+-dependent uptake velocity (10 s) was examined over a range of taurocholate concentration (0.036-0.9 mM), the plot described a rectangular hyperbola. The mean apparent Michaelis constant was 0.037 +/- 0.007 mM and maximum velocity was 1093 +/- 329 pmol taurocholate per milligram protein per 10 s. These data confirm and extend animal studies of ileal bile salt transport. Taurocholate uptake by the human ileal brush border occurs by a Na+-dependent, carrier-mediated electroneutral mechanism. According to this model, a single Na ion is coupled with a single taurocholate anion and transported across the brush border by a carrier mechanism that is driven by a transmembrane Na+ gradient.

Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells.

Selected G1 events associated with butyrate-induced differentiation were examined in HT-29 colon adenocarcinoma cells. [3H]Thymidine incorporation by HT-29 cells was decreased to 40% of control levels by treatment with 5 mM butyrate for 24 h, and cell numbers decreased to 21% of control levels after 48 h of treatment. Cells released from butyrate arrest entered S phase approximately 24 h after release, and serum-deprived HT-29 cells escaped growth inhibition if butyrate was added 8 h or more after serum restimulation. Northern analysis of RNA isolated from rapidly growing HT-29 cells showed a marked induction of alkaline phosphatase mRNA expression within 12 h of treatment with 5 mM butyrate. The appearance of alkaline phosphatase mRNA was temporally associated with a 5-fold increase in expression of transforming growth factor beta 1 (TGF-beta 1) mRNA. Expression of the nuclear protooncogene c-myc began to decrease 30 min after treatment with butyrate and was decreased 4.5-fold 4 h after treatment; however, expression of other immediate-early genes (nup/475 and zif/268) was not significantly affected. Histochemical staining of HT-29 monolayers showed that no cells were positive for alkaline phosphatase protein prior to treatment, and 90% were positive 48 h after treatment. TGF-beta 1 and TGF-beta 2 had no effect on HT-29 cell growth. TGF-beta 1 did not induce alkaline phosphatase mRNA or histochemical positivity. These data indicate that butyrate arrests HT-29 cell growth early in G1.(ABSTRACT TRUNCATED AT 250 WORDS)

Heparin binding epidermal growth factor-like growth factor is a transforming growth factor beta-regulated gene in intestinal epithelial cells.

Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an EGF-related peptide with prominent effects on cell growth and migration. We explored potentially unique characteristics of HB-EGF in the intestinal epithelial cell line RIE-1. HB-EGF stimulated [(3)H]thymidine incorporation to a level equivalent to transforming growth factor alpha (TGFalpha). HB-EGF also rapidly activated MAPK and induced cyclin D1 in mid-G1 with kinetics similar to TGFalpha. Unlike TGFalpha, HB-EGF mRNA was induced within 1 h by a variety of stimuli, including TGFbeta1. Maximal induction by TGFbeta (7-fold) occurred within 2 h of treatment. Actinomycin D decay curves showed that TGFbeta1 had no effect on HB-EGF mRNA half-life (T(1/2) 20 min). Induction of HB-EGF by TGFbeta1 was not affected by pretreatment with the MEK inhibitor PD-98059 while inhibition of protein kinase C either partially (calphostin C) or completely (staurosporin) blocked induction. Our results suggest that major differences exist in the regulation of the closely related EGF family members TGFalpha and HB-EGF. TGFbeta and HB-EGF, structurally unrelated peptides with potent effects on wound healing, may function coordinately to mediate responses to wounding or cell injury in the intestinal epithelium.

Methylprednisolone accelerates the ontogeny of sodium-taurocholate cotransport in rat ileal brush border membranes.

The effect of methylprednisolone on the postnatal maturation of taurocholate transport was studied by using isolated ileal brush border membrane vesicles. Vesicles were prepared from 14-day-old control, 14-day-old methylprednisolone-treated, and untreated 21-day-old rats. Methylprednisolone treatment resulted in a significant stimulation of taurocholate uptake by an inwardly directed Na+ gradient when compared with a choline gradient incubation. These differences occurred at 20 seconds and 1, 2, and 5 minutes of incubation (P less than 0.05). In 14-day-old controls, uptake was similar for Na+ and choline gradients. A plot of active uptake velocity vs. taurocholate concentration (0.1 to 1.0 mmol/L) in 14-day-old controls was linear and approached the abscissa, indicating the absence of active transport. Plots for methylprednisolone-treated rats showed saturability. An inwardly directed Na+ gradient stimulated initial taurocholate uptake rates by twofold at 37 degrees C (P less than 0.01), but not at 4 degrees C. Glycocholate and glycodeoxycholate inhibited Na+-stimulated taurocholate uptake by 50% (P less than 0.01) and 20% (P less than 0.05), respectively. These data indicate that pharmacologic doses of methylprednisolone accelerate the postnatal acquisition of Na+-dependent taurocholate cotransport in rat ileal brush border membranes.

Localization of transforming growth factor beta isoforms in the normal murine small intestine and colon.

BACKGROUND: The transforming growth factor beta (TGF-beta) proteins are key regulators of cellular growth and differentiation. Previous studies have shown that TGF-beta 1 is a potent growth inhibitor of cultured jejunal epithelial cells. The reported distribution of TGF-beta 1 messenger RNA (mRNA) expression along the intestinal villus has been controversial. The purpose of the current study is to determine the loci of TGF-beta protein expression in the normal small intestine and colon. METHODS: Intestinal localization of TGF-beta isoform mRNA and protein was examined by Northern blot analysis and immunohistochemistry using isoform specific reagents. RESULTS: TGF-beta 1, TGF-beta 2, and TGF-beta 3 mRNA were found in homogenates from the intact mouse jejunum and colon. The three isoforms colocalized in these tissues. Expression in the small intestinal epithelium was most prominent in cells located on the villus tip, and no staining was detected in the crypt. Occasional lymphocytes in the lamina propria were immunopositive, and all layers of the muscularis were moderately stained. This pattern was seen in all regions of the small intestine. The surface epithelium of the colon was intensely immunopositive, whereas cells in the glands were only weakly stained. CONCLUSIONS: TGF-beta molecules may serve overlapping functions in the intestinal tract, and expression in the epithelium may function to arrest growth of cells emerging from the crypt and induce or maintain the terminally differentiated state.