Improving Methods for Analyzing Antimalarial Drug Efficacy Trials: Molecular Correction Based on Length-Polymorphic Markers msp-1, msp-2, and glurp.

Drug efficacy trials monitor the continued efficacy of front-line drugs against falciparum malaria. Overestimating efficacy results in a country retaining a failing drug as first-line treatment with associated increases in morbidity and mortality, while underestimating drug effectiveness leads to removal of an effective treatment with substantial practical and economic implications. Trials are challenging: they require long durations of follow-up to detect drug failures, and patients are frequently reinfected during that period. Molecular correction based on parasite genotypes distinguishes reinfections from drug failures to ensure the accuracy of failure rate estimates. Several molecular correction "algorithms" have been proposed, but which is most accurate and/or robust remains unknown. We used pharmacological modeling to simulate parasite dynamics and genetic signals that occur in patients enrolled in malaria drug clinical trials. We compared estimates of treatment failure obtained from a selection of proposed molecular correction algorithms against the known "true" failure rate in the model. Our findings are as follows. (i) Molecular correction is essential to avoid substantial overestimates of drug failure rates. (ii) The current WHO-recommended algorithm consistently underestimates the true failure rate. (iii) Newly proposed algorithms produce more accurate failure rate estimates; the most accurate algorithm depends on the choice of drug, trial follow-up length, and transmission intensity. (iv) Long durations of patient follow-up may be counterproductive; large numbers of new infections accumulate and may be misclassified, overestimating drug failure rate. (v) Our model was highly consistent with existing in vivo data. The current WHO-recommended method for molecular correction and analysis of clinical trials should be reevaluated and updated.

Large-scale vibrating coil magnetometer for the magnetic characterization of bulk superconductors.

This work presents the design and validation of a vibrating coil magnetometer for the characterization of the field dependence of the critical current density of centimeter-sized bulk superconductors as an alternative to the destructive methods typically used. The magnetometer is also shown to be capable of measuring the magnetic moment in an applied field of up to 5 T for diverse magnetic materials, such as soft and hard ferromagnets and high-temperature superconducting pellets. The vibrating coil magnetometer was first optimized using finite element simulations and calibrated using a commercial vibrating sample magnetometer. The vibrating coil magnetometer was benchmarked with hysteresis measurements of a Nd2Fe14B disk made with a commercial hysteresisgraph, showing good agreement between the different setups. The magnetic hysteresis of a YBa2Cu3O7-x superconducting pellet was measured at 77 K, showing a penetration field of 1 T and an irreversibility field of 4 T. The field dependent critical current density of the superconductor was then inferred from the magnetic hysteresis measurements and extrapolated at low fields. Finally, the resulting critical current density was used to successfully reproduce the measured magnetization curve of the pellet at 2 T with finite element simulations.

Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease.

Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4α genetic variants and Crohn's disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the HNF4A gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case-control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33; P<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P<2.09 × 10(-4) for combined cohorts). This is the first report showing that the HNF4A locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD.

[Resistance of Plasmodium falciparum to antimalarial drugs: impact on malaria pre-elimination in Madagascar]. / Résistance de Plasmodium falciparum aux antipaludiques: impact sur la pré-élimination du paludisme à Madagascar.

The purpose of this review was to provide up-to-date information on the resistance of Plasmodium falciparum to the main antimalarials used in Madagascar and to assist implementation of the malaria control and elimination program. In 2006, the failure rate for chloroquine treatment was 44% (n = 300) and was comparable to the rate observed in continental Africa. Most treatment failures occurred after the first week of follow-up. P. falciparum resistance to chloroquine appeared to be special in Madagascar with only 3.2% of isolates showing in vitro resistance (n = 372, 7 sentinel sites) and less than 1% harbouring mutant parasites within the Pfcrt gene. Conversely, the Pfmdr1 N86Y point mutation was found in 64.3% (n = 174) of isolates in 2006 and in 51.7% (n = 343) in 2007. Failure of combined sulfadoxine-pyrimethamine therapy, i.e., the recommended intermittent preventive treatment for malaria during pregnancy, and in vitro resistance to pyrimethamine were rare. However, the Pfdhfr 51I/59R/108N allele showed consistently high prevalence levels reaching 33.3% in 2008. Moreover, the single Pfdhfr 164L mutant allele, a haplotype unique to Madagascar, was discovered in 2006 and showed prevalence rates up to 30% in some locations (southeast) in 2008. Up to now, the quadruple mutant allele Pfdhfr 51I/59R/108N/164L has not been observed. Susceptibility to the other antimalarials tested appeared excellent but the number of isolates showing in vitro susceptibility to artemisinin derivatives has been fallen in recent years and this decline may herald a decrease in the efficacy of these drugs.

[Acquired copper deficiency myelopathy]. / Myélopathie postérieure par carence en cuivre acquise.

INTRODUCTION: The hematological manifestations of acquired copper deficiency are well known. But the neurological manifestations have only been recognised in the past few years. The most common neurological manifestation in adults is a myeloneuropathy with prominent sensory ataxia and spastic gait. Electrophysiological tests reveal an axonal sensorimotor peripheral neuropathy. Spinal MRI shows an augmented T2 signal involving the dorsal column. The causes of acquired copper deficiency include gastric surgery, excessive zinc ingestion, and malabsorption but in most cases, the cause remains unclear. Early recognition and treatment may prevent neurological deterioration but improvement seems to be slight and inconstant. OBSERVATION: We report two new cases of acquired copper deficiency myeloneuropathy associated with a nephrotic syndrome and, in one case, with a major iron overload syndrome. Biological abnormalities disappeared under copper supplementation. A significant neurological improvement with disappearance of ataxia occurred in one patient who received copper supplementation eight months after symptom onset. CONCLUSIONS: Nephrotic syndrome might be another complication of acquired copper deficiency. Delayed treatment is not necessarily associated with a deleterious neurological prognosis. Significant neurological improvement under copper supplementation is possible.

Prospecting potential links between PRRSV infection susceptibility of alveolar macrophages and other respiratory infectious agents present in conventionally reared pigs.

Porcine Reproductive and Respiratory Syndrome virus (PRRSV) is one of the main component of the porcine respiratory disease complex (PRDC), which strongly impact the pig production. Although PRRSV is often considered as a primary infection that eases subsequent respiratory coinfections, the possibility that other PRDC components may facilitate PRRSV infection has been largely overlooked. The main cellular targets of PRRSV are respiratory macrophages among them alveolar macrophages (AM) and pulmonary intravascular macrophages (PIM). AM, contrarily to PIM, are directly exposed to the external respiratory environment, among them co-infectious agents. In order to explore the possibility of a co-infections impact on the capacity of respiratory macrophages to replicate PRRSV, we proceed to in vitro infection of AM and PIM sampled from animals presenting different sanitary status, and tested the presence in the respiratory tract of these animals of the most common porcine respiratory pathogens (PCV2, Actinobacillus pleuropneumoniae, Mycoplasma hyopneumoniae, Mycoplasma hyorhinis, Mycoplasma floculare, Pasteurella multocida, Bordetella bronchiseptica, Streptoccocus suis). In this exploratory study with a limited number of animals, no statistic differences were observed between AM and PIM susceptibility to in vitro PRRSV infection, nor between AM coming from animals presenting very contrasting respiratory coinfection loads.

Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities.

Anderson's disease (AD) or chylomicron retention disease (CMRD) is a rare hereditary lipid malabsorption syndrome linked to SARA2 gene mutations. We report in this study a novel mutation in two sisters for which the Sar1b protein is predicted to be truncated by 32 amino acids at its carboxyl-terminus. Because the SARA2 gene is also expressed in the muscle, heart, liver and placenta, extraintestinal clinical manifestations may exist. For the first time, we describe in this study in the two sisters muscular as well as cardiac abnormalities that could be related to the reported expression of SARA2 in these tissues. We also evaluated six other patients for potential manifestations of the SARA2 mutation. The creatine phosphokinase levels were increased in all patients [1.5-9.4 x normal (N)] and transaminases were moderately elevated in five of the eight patients (1.2-2.6 x N), probably related to muscle disease rather than to liver dysfunction. A decreased ejection fraction occurred in one patient (40%, N: 60%). The muscle, liver and placental tissues that were examined had no specific abnormalities and, in particular, no lipid accumulation. These results suggest that myolysis and other extraintestinal abnormalities can occur in AD/CMRD and that the clinical evaluation of patients should reflect this.

Magnetostatic interactions and coercivities of ferromagnetic soft nanowires in uniform length arrays.

First-order reversal curve diagrams have been used to investigate magnetostatic interactions and average coercivity of individual wires in soft ferromagnetic uniform length nanowire arrays. We present a method for identifying these physical parameters on the out-of-plane first-order reversal curve diagrams: the position of the irreversible part on the critical axis is a good approximation to the average value of the nanowire coercivity and the maximum interaction field is equal to the interaction field at saturation. Their dependence upon material (CoFeB and Ni) and nanowire length are presented. The magnetostatic interactions increase linearly with length, in agreement with a model developed previously. The global array coercivity, obtained from magnetization curves, is generally lower than the apparent average coercivity for individual nanowires. This coercivity reduction increases linearly with the magnetostatic interactions. The general shape of the out-of-plane first-order reversal curve diagrams is compared with those obtained from a theoretical moving Preisach model.

First order reversal curves (FORC) diagrams of Co nanowire arrays.

Nanowire arrays of Co and Ni have been obtained by current pulse electrodeposition into nanoporous alumina templates. By adjusting the pH of the bath, the microstructure of the Co wires was tailored, resulting in two types of arrays of crystalline Co--hcp, with c-axis nominally parallel (Co (c parallel)), or nominally perpendicular (Co (c perpendicular)) to the wire. First-order reversal curve (FORC) diagrams provide information on average coercivity of the individual nanowire and the factors influencing the field created in the saturated array by the magnetostatic interactions. The dependences of this field on array geometry (wire length and diameter) and saturation magnetization were found to be in excellent agreement with theoretical predictions from a micromagnetic model. For arrays with lower wire diameter, the average coercivity of the individual wires is systematically higher than the coercivity of the array. The most important difference between the two Co series is in the dependence of the FORC diagrams on the wire diameter, with the Co (cl) showing significant pattern changes at large diameters. Two possible sources of those changes are discussed.

Efficacy of chloroquine-proguanil malaria prophylaxis in a non-immune population in Bangui, Central African Republic: a case-control study.

A case-control study was conducted to evaluate the efficacy of the combination of chloroquine plus proguanil as malaria prophylaxis in a non-immune population living in the Central African Republic. Cases were patients presenting with a malaria attack confirmed by a positive blood film and/or an HRP2 positive antigen test at the Pasteur Institute of Bangui. Two control subjects were included per case: one was a relative or close friend and the other was matched to the patient with respect to the length of stay. A questionnaire assessing malaria prophylaxis habits and malarial risk factors over the 2-month period prior to inclusion in the study was given to 48 cases and 96 controls. A conditional logistic regression was used to identify risk factors. The efficacy of the chloroquine plus proguanil regimen was found to be high (95.5%, 95% CI 74.0-99.2%) in this country known for high chloroquine resistance. Our data lend some support to the use of chloroquine plus proguanil in Bangui, and the protective efficacy of chloroquine plus proguanil should now be studied prospectively as part of a randomised controlled trial of various prophylactic drugs.

[Multiple and successive treatment failures in a patient infected by Plasmodium falciparum in Cambodia and treated by dihydroartemisinin-piperaquine]. / Echecs thérapeutiques multiples et successifs chez un patient infecté par Plasmodium falciparum au Cambodge et traité par dihydroartémisinine-pipéraquine.

Cases of treatment failures following administration of artemisinin-based combination therapies (ACT) remain rare in malaria endemic areas. In Cambodia, however, failures of these treatments are now commonly observed. Usually, these post-treatment recurrences occur only once and a second course of the same treatment is sufficient to cure patients.We describe here an atypical case of a Plasmodium falciparum-infected patient manifesting several malaria recrudescence episodes following dihydroartemisinin-piperaquine (Eurartesim®) treatment. This case report illustrates the current issue of resistance to the latest generation of antimalarial drugs in Southeast Asia and highlights the difficulty in efficaciously fighting malaria in this region if new therapy remains unimplemented.

Transcriptional changes in Crassostrea gigas oyster spat following a parental exposure to the herbicide diuron.

The Pacific oyster Crassostrea gigas is the main oyster species produced in the world, and a key coastal economic resource in France. High mortalities affect Pacific oysters since 2008 in France and Europe. Their origins have been attributed to a combination of biotic and abiotic factors, underlining the importance of environment quality. The impact of water pollution has been pointed out and one of the pollutants, the genotoxic herbicide diuron, occurs at high concentrations all along the French coasts. Previous work has revealed that a parental exposure to diuron had a strong impact on hatching rates and offspring development even if spats were not exposed to diuron themselves. In this study, we explored for the first time the transcriptional changes occurring in oyster spats (non exposed) originating from genitors exposed to an environmentally relevant concentration of diuron during gametogenesis using the RNAseq methodology. We identified a transcriptomic remodeling revealing an effect of the herbicide. Different molecular pathways involved in energy production, translation and cell proliferation are particularly disturbed. This analysis revealed modulated candidate genes putatively involved in response to oxidative stress and mitochondrial damage in offspring of genitors exposed to diuron. Complementary measures of the activity of enzymes involved in these latter processes corroborate the results obtained at the transcriptomic level. In addition, our results suggested an increase in energy production and mitotic activity in 5-month-spats from diuron-exposed genitors. These results could correspond to a "catch-up growth" phenomenon allowing the spats from diuron-exposed genitors, which displayed a growth delay at 3 months, to gain a normal size when they reach the age of 6 months. These results indicate that exposure to a concentration of diuron that is frequently encountered in the field during the oyster's gametogenesis stage can impact the next generation and may result in fitness disturbance.

Effects of an environmentally relevant concentration of diuron on oyster genitors during gametogenesis: responses of early molecular and cellular markers and physiological impacts.

Genitors of the Pacific oyster Crassostrea gigas were submitted during gametogenesis to a short pulse exposure to the herbicide diuron at a realistic environmental concentration. Histological analysis showed no effect of diuron on gametogenesis course, sex ratio and reproductive effort. A non-significant increase in testosterone and progesterone levels was observed in genitors exposed to the herbicide. At cell level, diuron exposure was shown to modulate the phagocytic activity of circulating hemocytes. The results of a transcriptional analysis showed that diuron affected the expression of genes belonging to functions known to play a major role during oyster gametogenesis such as gene transcription regulation, DNA replication and repair, DNA methylation and cytokinesis. Taking into account the results we previously obtained on the same genitors, this study showed a negative effect of diuron on oyster reproduction by inducing both structural and functional modifications of the DNA.

Insulin decreases chylomicron production in human fetal small intestine.

The objective of this study was to examine the effect of insulin on lipoprotein synthesis and secretion in human fetal intestine. Jejunal explants were cultured with [14C]oleic acid in Leibovitz medium for 42 h. Although the addition of insulin (30 U) did not alter the incorporation of [14C]oleic acid into triglycerides, phospholipids and cholesteryl esters in the tissue, it significantly decreased (P < 0.05) the level of triglycerides (20%) in the medium. Among the three lipoprotein classes (chylomicron, VLDL, and HDL) isolated by ultracentrifugation, the chylomicron level was found significantly (P < 0.05) diminished in the medium (29%). Neither the lipid chemical composition of CM or that of VLDL, LDL and HDL was affected by the presence of insulin. These results suggest that chylomicron synthesis is modulated by insulin, whereas lipoprotein distribution and lipid composition are not regulated by this hormone.

Endogenous lipase activity in Caco-2 cells.

Dietary triglycerides, the major precursors of long chain fatty acids (FA), require hydrolysis by pancreatic enzymes prior to their absorption by the small intestine. Although Caco-2 cells are frequently employed for the study of enterocyte lipid metabolism, the presence of an endogenous lipase activity has never been previously reported. The major goal of this investigation was to determine the presence of endogenous Caco-2 cell lipase activity, to examine its capacity to hydrolyze triglycerides, and to define its intracellular location. Caco-2 cells were found to have an endogenous lipase activity, capable of hydrolyzing [1-14C]triolein from the apical cell compartment. A time and concentration dependence of lipase activity was observed, with hydrolysis of triolein into free fatty acids and monoglyceride. The majority of the lipase activity was found in the cytosolic cell fraction and, to a lesser extent, in the apical brush border membrane and other organelles. Protamine sulfate markedly reduced the Caco-2 cell lipase activity, yet it remained relatively insensitive to high concentrations of NaCl, taurocholate, calcium, heparin and chloroquine. The addition of exogenous human gastric lipase to the medium of the apical compartment resulted in a significant increased rate of hydrolysis of triolein, followed by enhanced Caco-2 cell fatty acid uptake and basolateral lipid secretion. The major esterified intracellular lipids were triglycerides and phospholipids. We conclude that Caco-2 cells possess an endogenous lipase capable of hydrolyzing cytosolic triglycerides. Furthermore, activity present on the apical membrane and secreted into the apical medium, though quantitatively less important than the cytosolic lipase, may permit an additional route for energy uptake. The addition of gastric lipase to the Caco-2 cell cultures greatly enhanced FA uptake above that seen with the endogenous lipase alone.

Caco-2 cells and human fetal colon: a comparative analysis of their lipid transport.

Caco-2 cells and human colonic explants were compared for their ability to esterify lipid classes, synthesize apolipoproteins and assemble lipoproteins. Highly differentiated cells and colonic explants were incubated with [(14)C]oleic acid or [(35)S]methionine for 48 h. Caco-2 cells demonstrated a higher ability to incorporate [(14)C]oleic acid into cellular phospholipids (13-fold, P<0.005), triglycerides (28-fold, P<0.005) and cholesteryl ester (2-fold, P<0. 01). However, their medium/cell lipid ratio was 11 times lower, indicating a limited capacity to export newly synthesized lipids. De novo synthesis of apo B-48 and apo B-100 was markedly increased (7%0 and 240%, respectively), whereas the biogenesis of apo A-I was decreased (60%) in Caco-2 cells. The calculated apo B-48/apo B-100 ratio was substantially diminished (107%), suggesting less efficient mRNA editing in Caco-2 cells. When lipoprotein distribution was examined, it displayed a prevalence of VLDL and LDL, accompanied along with a lower proportion of chylomicron and HDL. In addition, differences in lipoprotein composition were evidenced between colonic explants and Caco-2 cells. Therefore, our findings stress the variance in the magnitude of lipid, apolipoprotein and lipoprotein synthesis and secretion between the two intestinal models. This may be due to various factors, including the origin of Caco-2 cell line, i.e., colon carcinoma.

Effects of captopril and minoxidil on left ventricular hypertrophy in resistant hypertensive patients: a 6 month double-blind comparison.

In a double-blind 6 month trial, the cardiac effects of captopril and minoxidil, administered as third step treatments, were compared in 34 men with essential hypertension and diastolic blood pressure greater than 95 mm Hg who were taking 200 mg/day of metoprolol and 80 mg/day of furosemide. Average daily doses of captopril and minoxidil were 269 mg (range 150 to 300) and 20 mg (range 7.5 to 30), respectively. At the end of the 6 months' treatment, blood pressure had dropped significantly in both groups, but echocardiographic criteria of hypertrophy improved only in the captopril group (intragroup comparison): blood pressure, thickness of the intraventricular septum and posterior wall, and the left ventricular mass index, respectively, decreased from 163/102 to 135/89 mm Hg (p less than 0.001), 17.4 to 15.9 mm (p less than 0.05), 14.5 to 13.4 mm (p less than 0.05) and 236 to 198 g/m2 (p less than 0.001). In the minoxidil group, blood pressure dropped from 160/99 to 137/87 mm Hg (p less than 0.001), but echocardiographic criteria were not significantly modified. Fractional shortening remained normal in both groups. These results show that in patients with severe left ventricular hypertrophy, captopril-based triple therapy reduces left ventricular mass without altering systolic performance, whereas minoxidil-based therapy does not.

Coordinated control of fetal gastric epithelial functions by insulin-like growth factors and their binding proteins.

The influence of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) on human gastric functions are unknown. This study was undertaken to evaluate the ability of fetal gastric mucosa to produce IGFBPs and to test the effects of IGF-I, IGF-II, and synthetic truncated IGFs that do not interact with IGFBPs on epithelial cell proliferation and glandular zymogenic function. Western blots, Far Western blots, and immunohistochemistry were performed to characterize the expression of IGFBP-1 to -6 and IGF-I receptor. The effects of growth factors on DNA synthesis and lipase and pepsin activities were determined in gastric explants maintained in serum-free organ culture. All gastric epithelial cells expressed the IGF-I receptor. IGFBP-2 to -6 were produced endogenously, and they were differentially localized along the foveolus-gland axis and modulated in culture. Exogenous IGF-I and IGF-II were able to reduce lipase activity without affecting pepsin, whereas they exerted different effects on cellular proliferation: IGF-I was stimulatory and IGF-II had no influence. Illustrating the complex regulatory effect that IGFBPs exert on IGF bioactivity, both truncated IGF-I and IGF-II stimulated DNA synthesis more than IGF-I. Moreover, the striking difference in mitogenic activity between truncated and native forms of IGF-II probably reflects the abundance of IGFBP-2 and IGFBP-6, two IGF-II carriers, in the foveolus/neck region, including the proliferative compartment. This study provides new evidence for the involvement of an intragastric IGF/IGFBP system in the fine regulation of epithelial cell division and also in the control of zymogen synthesis. Moreover, the specific influence of IGF-II as a mitogen appears to be tightly regulated by IGFBP isoforms preferentially associated with this growth factor and proliferative cells.

Epidermal growth factor receptors during postnatal development of the mouse colon.

The present study was undertaken to establish the postnatal profile of specific epidermal growth factor (EGF) binding in the maturing mouse colon, with particular emphasis on possible regional differences between both proximal and distal colonic binding patterns vs. those of the small intestine. Binding studies using [125I]EGF were performed on isolated epithelial cells obtained from 2-, 5-, 9-, 16-, and 22-day-old mice as well as adults. At 2 days, cells isolated from the entire colon bound 4 times more [125I]EGF than did corresponding intestinal cells, whereas between the ages of 5 days to adult, colonic cells bound between 1.7-2.5 times more labeled EGF than their intestinal counterparts. The immature colon already exhibited maximal binding after birth as opposed to the small intestine where binding only reached maximal values by the third week of life. Comparison between the proximal and distal colon in 9-, 16-, and 22-day-old mice revealed a further 2-fold increase in EGF binding in the distal colon compared to that in the proximal colon. Scatchard plots of [125I]EGF displacement by native EGF in both proximal and distal colonic segments also revealed the presence of two classes of binding sites, with high affinity constants (K1) significantly greater in the distal colon. These results demonstrate for the first time not only the continued presence of EGF receptors in mouse colonic epithelium, but also significant regional differences in EGF-binding capacity within the digestive tract throughout the postnatal period.

Presence and characteristics of epidermal growth factor receptors in human fetal small intestine and colon.

In the present study, we demonstrate for the first time the presence of important concentrations of EGF binding sites in isolated epithelial cells of both human fetal small intestine and colon as early as 12 weeks gestation. The pattern of EGF binding in the small intestine between 12 and 17 weeks show that binding was significantly higher (2.5-fold) in younger fetuses than in older fetuses. Moreover, the fetal colon exhibited a much higher binding capacity (1.5-2.5 times) than corresponding intestinal cells for all age groups studied. Analysis of Scatchard representations reveal that the concentration of high- and low-affinity binding sites in colonic epithelial cells are twice the values observed in corresponding intestinal cells. The present data raise interesting possibilities as to the role of this growth factor in human fetal gut development.