19 As the low FODMAP diet was lower in RS than the high FODMAP diet, wheat muffins containing high amylose maize (high in RS) were added to balance the RS content. An example of the test diets provided on day 2 of the study is shown in Table 1. All food used was purchased from the local supermarket with the exception of the 355 mL can of soda that was sweetened with high fructose corn syrup (imported from the USA) and was

obtained from a specialty supermarket. Samples of food and drinks used in the study were separately analyzed for their content of fructose, glucose, lactose, sugar polyols (sorbitol and mannitol), GSI-IX order galacto-oligosaccharides (GOS, raffinose and stachyose) by high performance liquid chromatography

(HPLC) as previously described.20 Total fructan content was measured using an enzymatically-based assay kit (Megazyme International Ireland Ltd, Wicklow, Ireland), as per the manufacturer’s instructions.21 Results from laboratory analysis were added to the Foodworks database (Foodworks Professional 2007, Xyris Software, Highgate Hill, QLD, Australia) to enable the complete assessment of the macronutrient A 769662 and FODMAP dietary intake during the study. Breath samples were collected every hour for 14 h into 250 mL sample holding bags (Quintron Instrument Co., Milwaukee, Wisconsin). The first sample of the day was a fasting sample and taken prior to breakfast. Samples were then taken hourly for a total of 14 h. All of the supplied food was to be consumed within the 14-h time period. The exact time each subject consumed their meals varied slightly between individuals but was kept constant within each individual during the two dietary medchemexpress periods (i.e. each person was their own control in the crossover design). Breath samples were analyzed for

hydrogen and methane within 24 h using a Quintron Microlyzer Model DP Plus (Quintron Instrument Co., Milwaukee, WI, USA). Total breath gas production over the 14-h period was then calculated from the graphed area-under-the-curve (AUC) using the trapezium rule and expressed in parts per million over 14 h (ppm.14 h). A subject was considered to produce hydrogen or methane if the AUC was more than 10 ppm.14 h during at least one of the dietary periods. All subjects were asked to complete the gastrointestinal symptom questionnaire at the same time in the evening of each day. The questionnaire comprised five categories for general gastrointestinal symptoms (abdominal pain/discomfort, abdominal bloating/distension, wind, nausea, heartburn and lethargy). Bowel function was noted but not analyzed due to the heterogeneity of bowel habits across the subjects. The symptoms were rated using a Likert scale 0 to 3, where 0 = none, 1 = mild, 2 = moderate and 3 = severe.

Similar results were also reported by Ozkasap et al. [36] who demonstrated that H. pylori eradication significantly reduces the levels of hepcidin, possibly by increasing the response to iron therapy. On the other hand, Kim et al. [37] did not find any significant association between H. pylori infection and serum levels of prohepcidin, while this biomarker was decreased in patients with atrophic gastritis. Finally, the results of three recent studies did not support any association between H. pylori infection and IDA [38-40]; however, the occurrence of some biases, such as the exact definition of IDA or the absence of information concerning the specific gastric histologic

patterns shown by patients, may, in our selleck chemical opinion, affect the results of studies performed on this important issue. The role of H. pylori on idiopathic thrombocytopenic purpura (ITP), via the modulation of Fcγ-receptor balance of monocytes/macrophages or molecular mimicry mechanisms between platelet and H. pylori peptides, is well defined [41]. A study by Payandeh et al. [42] clearly reported a significant beneficial effect of H. pylori eradication in patients with mild thrombocytopenia, but a poor response in patients with severe thrombo-cytopenia was noted. In a similar study, Teawtrakul et al. [43] showed a significant platelet count response

in approximately 80% of GSK-3 cancer adults with ITP after H. pylori eradication within a median time of 4 months. Nevertheless, some authors

reported negative findings. Samson et al. [44] did not show any significant difference between infected and noninfected patients concerning the platelet count, while Gan et al. [45] reported a low prevalence of H. pylori infection in patients with ITP and the absence of any significant effect of H. pylori eradication on the platelet count. Differences in the definition MCE of ITP may be the cause of those findings, at least in our opinion. A meta-analysis by Shi et al. [46] conducted on patients with autoimmune thyroid disease (ATD) reported a significant role of H. pylori in Grave’s disease (GD), more than in Hashimoto’s thyroiditis (HT), with an additional increased risk in the case of infection sustained by CagA-positive strains. Another study by Aghili et al. [47] reported a significant epidemiological association between H. pylori infection and HT in patients from Iran. Similarly, Zekry et al. [48] demonstrated a significant association between H. pylori infection and autoimmune thyroiditis in patients affected by type 1 DM. An additional interesting study clearly showed a significant association between GD, CagA positivity, and negative HLA-DQA1 0201 or positive HLA-DQA1 0501 [49]. Finally, Jafarzadeh et al. [50] reported higher serum levels of rheumatoid factor and antinuclear antibodies in H.

[28-31] The sumatriptan iontophoretic transdermal system (Zecuity®, sumatriptan TDS, NuPathe, Inc., http://www.selleckchem.com/products/chir-99021-ct99021-hcl.html Conshohocken, PA, USA), which was developed to address the unmet needs of migraine patients, particularly those with MRN, employs iontophoretic technology to deliver sumatriptan, the most widely used treatment for migraine. Sumatriptan TDS, which circumvents the GI tract by using low-level electrical energy to transport

sumatriptan across the skin, provides clinical benefits in migraine without the need for oral, intranasal, or subcutaneous administration[32] by relying on proprietary iontophoretic technology. Migraine patients apply sumatriptan TDS to the upper arm or thigh, and the activated system drives ionized sumatriptan into the bloodstream at controlled rates over 4 hours (Fig. 1 —), resulting in a predictable pharmacology and efficacy. The pharmacological and clinical profiles of sumatriptan TDS have been characterized in multiple well-controlled studies. Selleck Tyrosine Kinase Inhibitor Library In a single-center, open-label, cross-over study, Pierce and colleagues

compared the pharmacokinetic (PK) profiles of the oral (100 mg), intranasal (20 mg), and subcutaneous (6 mg) formulations of sumatriptan with sumatriptan TDS in 25 healthy volunteers aged 21-57 years.[32] The area under the drug concentration-time

curve (AUC) for sumatriptan TDS was similar to the subcutaneous formulation, but it had a lower maximum observed drug concentration (Cmax), which decreased the relative risk 上海皓元医药股份有限公司 of triptan-like sensations believed to be attributable to peak plasma concentrations. Moreover, because the transdermal and subcutaneous formulations had lower coefficients of variation than the oral and intranasal formulations (Table 1), they achieved and sustained more predictable target drug levels.[32] Sumatriptan was detected in plasma within 15 minutes after activation of sumatriptan TDS, it reached plasma concentrations of 10 ng/mL by approximately 30 minutes after patch activation, and it maintained concentrations of approximately 20 ng/mL until 4 hours post-activation. Over the 4-hour study period, the mean drug delivery for sumatriptan TDS was approximately 6.1 mg. When drug delivery was stopped at 4 hours post-activation, steady declines in serum concentration for sumatriptan matched the gradual reductions in plasma concentrations following administration of the oral and intranasal formulations.[32] Other investigations have extended these early findings.

Bizarre structures are common in many fishes, as well as other reptiles. In birds, sexual dimorphism, display and selection are well-established phenomena that have clearly had a very strong role in shaping avian evolution. The expression of bizarre structures

in mammals, notably ungulates, is entailed in a constellation of ecological characteristics that greatly complicate their explanation (Jarman, 1974; Perez-Barberia, Lorlatinib Gordon & Pagel, 2002). Finally, we emphasize that a given structure may have several purposes, and that even in living animals it is often difficult to determine the uses of particular structures, their evolutionary histories, and even how the animals are communicating. In this respect the hypotheses of paleobiologists are largely interpreting the shadows on the wall of Plato’s cave. We persist in efforts to explain these structures because they were of obvious use to their bearers, and this is in principle discoverable. We thank S. Bar-David, J. Brashares, V. de Buffrenil, K. Carpenter, P. Cross, P. check details Dodson, J.O. Farlow, E. Hebets, T. Hieronymus, R. Irmis, C. Janis, E. Lacey, B. Lundrigan, S. Patek, A. de Ricqlès, M.J. Ryan, S.M. Sampson, K.M. Scott, A.B. Shabel, L.M. Witmer and many other colleagues and

reviewers for constructive comments and suggestions, without implying their agreement with all our points. UCB undergraduates Jasmeet K. Dhaliwal and Sylvia Moses provided research support. R. Irmis and A. Lee provided technical support. This work was supported by the University of California Museum of Paleontology and the Committee on Research of the University of California, Berkeley. This is UCMP Contribution No. 2012. “
“Wild ruminants may differ in their protozoal fauna according to their

feeding type, 上海皓元医药股份有限公司 but a comprehensive evaluation of available data is lacking. Here, we evaluate the literature data available on the protozoal fauna (diversity, concentration and proportions of the major groups including Entodiniinae, Diplodiniinae and Isotrichidae) in relation to the natural diet (as percentage of grass in the natural diet, %grass) and body mass (BM) in 55 wild ruminant species. The effects of ruminant phylogeny were controlled for using phylogenies based on molecular data and phylogenetic generalized least-squares. Transferring results from domestic to wild ruminants, we hypothesized (1) a decrease in the proportion of Entodiniinae and an increase in that of Diplodiinae, with %grass in the natural diet; (2) a positive correlation between Diplodiinae and Isotrichidae; (3) no influence of BM on these protozoal groups. Based on the literature statements, we additionally expected that (4) protozoa diversity increased with %grass and BM and that (5) protozoa concentrations were independent of both BM but decreased with %grass. Only hypothesis 1 was confirmed completely. Isotrichidae and Diplodiinae only tended to correlate (P=0.08), but the proportion of Isotrichidae increased with BM.

See the Supporting Materials and Methods for details regarding DNA sequencing, HGF immunoassay, flow cytometry, and cell viability analysis. The Student t test was used to compare data between two groups. Analysis of variance was used to evaluate see more the difference among multiple groups. A prior report demonstrated that MHCC97-L and MHCC97-H cell lines have low and high metastatic

potential, respectively.25 Given the current hypothesis proposed by Thiery31 and Bernards and Weinberg32 that links a mesenchymal phenotype to metastasis, we investigated whether metastatic HCC cells have mesenchymal features in comparison with nonmetastatic Huh7 and Hep3B cells.33 In terms of morphology, MHCC97-L and MHCC97-H cells demonstrated a fibroblast-like appearance, whereas Huh7 and Hep3B cells displayed a cobblestone appearance (Fig. 1A). In terms of gene expression, MHCC97-L and MHCC97-H cells demonstrate low E-cadherin expression, consistent with a mesenchymal phenotype, and high expression of

E-cadherin repressor Zeb2 compared with Huh7 and Hep3B cells (Fig. 1B). There was no significant difference in expression of Snail, Twist, and Zeb1 between the four cell lines (data not shown). Protein expression confirmed a mesenchymal phenotype in MHCC97-L and MHCC97-H cells, with decreased E-cadherin expression and increased fibronectin expression (Fig. 1C). The mesenchymal phenotype of MHCC97-L and MHCC97-H cells correlates with strong expression and constitutive phosphorylation of c-Met (Fig. 1B,C). Several published reports have indicated that HIF inhibitor mutations in the c-Met gene correlate with activation in multiple different cancers.20-22 Therefore, we investigated whether the activation of c-Met in MHCC97-L and MHCC97-H cells was due to a mutation. Sequencing of the c-Met gene demonstrated none of the reported

mutations, as identified through alignment analysis (Supporting Materials and Methods, data not shown). Because sequencing demonstrated no previously reported mutation, we hypothesized that the activation was due to autocrine secretion of HGF. MCE An analysis of secreted proteins in conditioned media failed to demonstrate any HGF secreted by MHCC97-L and MHCC97-H cells (Supporting Materials and Methods, data not shown). Thus, the precise mechanism of c-Met activation in MHCC97-L and MHCC97-H cells remains unknown. Constitutive activation or HGF-stimulated tyrosine phosphorylation of c-Met is blocked by PHA665752, a small molecular compound that functions as a selective inhibitor of c-Met phosphorylation26 in gastric, lung, and pancreatic cancer cells.27 Using PHA665752, we investigated the effect of tyrosine kinase inhibition on the activation of c-Met and downstream signaling pathways in human HCC. As shown in Fig. 2, PHA665752 treatment eliminated c-Met phosphorylation at multiple tyrosine residues (Y1234/Y1234 and Y1349) and reduced downstream phosphorylation of Akt and Erk (P44/42) in c-Met–positive MHCC97-L and MHCC97-H cells.

See the Supporting Materials and Methods for details regarding DNA sequencing, HGF immunoassay, flow cytometry, and cell viability analysis. The Student t test was used to compare data between two groups. Analysis of variance was used to evaluate Buparlisib purchase the difference among multiple groups. A prior report demonstrated that MHCC97-L and MHCC97-H cell lines have low and high metastatic

potential, respectively.25 Given the current hypothesis proposed by Thiery31 and Bernards and Weinberg32 that links a mesenchymal phenotype to metastasis, we investigated whether metastatic HCC cells have mesenchymal features in comparison with nonmetastatic Huh7 and Hep3B cells.33 In terms of morphology, MHCC97-L and MHCC97-H cells demonstrated a fibroblast-like appearance, whereas Huh7 and Hep3B cells displayed a cobblestone appearance (Fig. 1A). In terms of gene expression, MHCC97-L and MHCC97-H cells demonstrate low E-cadherin expression, consistent with a mesenchymal phenotype, and high expression of

E-cadherin repressor Zeb2 compared with Huh7 and Hep3B cells (Fig. 1B). There was no significant difference in expression of Snail, Twist, and Zeb1 between the four cell lines (data not shown). Protein expression confirmed a mesenchymal phenotype in MHCC97-L and MHCC97-H cells, with decreased E-cadherin expression and increased fibronectin expression (Fig. 1C). The mesenchymal phenotype of MHCC97-L and MHCC97-H cells correlates with strong expression and constitutive phosphorylation of c-Met (Fig. 1B,C). Several published reports have indicated that BAY 57-1293 chemical structure mutations in the c-Met gene correlate with activation in multiple different cancers.20-22 Therefore, we investigated whether the activation of c-Met in MHCC97-L and MHCC97-H cells was due to a mutation. Sequencing of the c-Met gene demonstrated none of the reported

mutations, as identified through alignment analysis (Supporting Materials and Methods, data not shown). Because sequencing demonstrated no previously reported mutation, we hypothesized that the activation was due to autocrine secretion of HGF. MCE An analysis of secreted proteins in conditioned media failed to demonstrate any HGF secreted by MHCC97-L and MHCC97-H cells (Supporting Materials and Methods, data not shown). Thus, the precise mechanism of c-Met activation in MHCC97-L and MHCC97-H cells remains unknown. Constitutive activation or HGF-stimulated tyrosine phosphorylation of c-Met is blocked by PHA665752, a small molecular compound that functions as a selective inhibitor of c-Met phosphorylation26 in gastric, lung, and pancreatic cancer cells.27 Using PHA665752, we investigated the effect of tyrosine kinase inhibition on the activation of c-Met and downstream signaling pathways in human HCC. As shown in Fig. 2, PHA665752 treatment eliminated c-Met phosphorylation at multiple tyrosine residues (Y1234/Y1234 and Y1349) and reduced downstream phosphorylation of Akt and Erk (P44/42) in c-Met–positive MHCC97-L and MHCC97-H cells.

Effective telaprevir minimum were plasma concentrations (Cmin) approximately five-fold higher than the 90% maximal effective concentration (EC90) as determined by the replicon system.8 Therefore, in order to selleck achieve narlaprevir exposures that would demonstrate potent antiviral activity, the doses administered in this study (800 mg narlaprevir three times daily and 400 mg narlaprevir with 200 mg ritonavir twice daily) were targeted to attain a therapeutic exposure and a mean Cmin at least five- to 10-fold above the replicon assay EC90 value of 40 nM (≈28 ng/mL). We report the safety and tolerability

of narlaprevir administered at two dose levels as monotherapy and in combination with PEG-IFN-α-2b in 40 treatment-naïve and treatment-experienced patients infected with HCV genotype 1. We also present the antiviral activity and pharmacokinetic profile of narlaprevir and the response to SOC (PEG-IFN-α-2b/RBV) following the completion of narlaprevir administration. AE, adverse event; Cmin, minimum plasma concentration; CYP3A4, cytochrome P450-3A4; EC90, 90% maximal effective concentration; HCV, hepatitis C virus; HIV, human immunodeficiency virus; NS3, nonstructural protein 3; PEG-IFN-α-2b, pegylated interferon α-2b; RBV, ribavirin; RVR, rapid viral response; SOC, standard of care; SVR, sustained virological Pembrolizumab in vitro response.

This randomized, placebo-controlled, double-blind, two-period phase 1b study was conducted at three sites in The Netherlands. Narlaprevir dosing was conducted at a single site as an inpatient study; SOC was administered on an outpatient basis. Study medication (PegIntron, Rebetol, and narlaprevir) was supplied by Schering-Plough Research Institute. Ritonavir (Norvir; Abbott

Laboratories) was also used in this study. Narlaprevir and matched-placebo were administered as an amorphous suspension. The study was conducted as a two-period, fixed-sequence study in 40 HCV genotype 1–infected patients enrolled in four cohorts (Fig. 1). Cohorts 1 and 3 each included 10 patients naïve to HCV treatment; cohorts 2 and 4 each included 10 HCV treatment-experienced patients. In each cohort, patients 上海皓元医药股份有限公司 were randomized in a 4:1 ratio to either narlaprevir (n = 8) or placebo (n = 2) according to a computer-generated random code. Treatment was prepared and dispensed in a blinded fashion by a third party for administration to the patients. The third party was not involved with the study procedures, assessments, or data recording and did not reveal the randomization during the study according to the Consolidated Standards of Reporting Trials guidelines.19 During period 1, patients received either 800 mg narlaprevir (or placebo) three times daily (cohorts 1 and 2) as monotherapy or 400 mg narlaprevir (or placebo) in combination with 200 mg ritonavir twice daily (cohorts 3 and 4) for 7 consecutive days. There was a washout period of approximately 4 weeks between the final treatment administration in period 1 and the first treatment in period 2.

[23] Our study was designed to examine the response to visual stimulation with a rotating optokinetic drum in migraine patients compared with healthy controls by using both fMRI with its high spatial resolution and fTCD providing a high temporal resolution, thereby assessing changes in the activation

pattern of the visual cortex with attention to extrastriate areas relevant for motion processing as well as in the functional vasomotor reactivity and their lateralization. Eighteen patients (13 women, age range 18–54 years, mean 36.0 ± 11.8) with migraine with aura (MA) according to the diagnostic criteria of the International Headache Society[24] and 18 age- and sex-matched Cytoskeletal Signaling inhibitor healthy controls with no history of neurological or psychiatric disease (13 women, age range 21–55, mean 36.5 ± 11.4) were recruited for the study. All subjects were right-handed. Patients were studied in a headache-free period, at least

72 hours after the last attack. The local Institutional Review Board (Medical Ethics Committee II, Medical Faculty Mannheim, University of Heidelberg) approved the study. Informed consent was obtained in written form from all subjects. For the subjects’ characteristics, see Table 1. The visual stimulus for both fMRI and fTCD examination was a vertically rotating optokinetic drum with complex colored comic figures, as described in previous studies.[3, 20] Subjects were instructed to look at and pursuit the moving images on the drum revolving 10 times per minute. Functional TCD and MRI measurements were Ku-0059436 price conducted consecutively in the same session. As first examination, we performed

the trans-temporal TCD recording from the P2 segments of both posterior cerebral arteries (PCA) simultaneously with a four-channel TCD scanner (DWL Multidop X, Compumedics Germany GmbH, Singen, Germany) with 2-MHz pulsed-wave Doppler 上海皓元 transducers affixed to a headband during visual stimulation with 10 averaged cycles of a 20-second “on” phase followed by a 20-second “off” phase (eyes closed). During the subsequent fMRI measurement, the stimulus was presented as a movie with the use of the “integrated functional imaging system” (Invivo, Orlando, FL, USA) via a liquid crystal display screen attached to the MRI head coil (see Fig. 1 —). Subjects with visual impairment were provided with MR-compatible corrective lenses. The MR scan was performed on a 1.5-T whole body scanner (Magnetom Sonata, Siemens Medical, Erlangen, Germany). A three-dimensional T1w whole brain data set was acquired (magnetization-prepared rapid gradient echo imaging; repetition time [TR]/echo time [TE]/flip angle/field of view [FOV] = 1.800 milliseconds/3.33 milliseconds/8°/240 mm) for anatomical reference with a voxel size of 1.3 × 1.3 × 1.2 mm3.

[23] Our study was designed to examine the response to visual stimulation with a rotating optokinetic drum in migraine patients compared with healthy controls by using both fMRI with its high spatial resolution and fTCD providing a high temporal resolution, thereby assessing changes in the activation

pattern of the visual cortex with attention to extrastriate areas relevant for motion processing as well as in the functional vasomotor reactivity and their lateralization. Eighteen patients (13 women, age range 18–54 years, mean 36.0 ± 11.8) with migraine with aura (MA) according to the diagnostic criteria of the International Headache Society[24] and 18 age- and sex-matched R788 solubility dmso healthy controls with no history of neurological or psychiatric disease (13 women, age range 21–55, mean 36.5 ± 11.4) were recruited for the study. All subjects were right-handed. Patients were studied in a headache-free period, at least

72 hours after the last attack. The local Institutional Review Board (Medical Ethics Committee II, Medical Faculty Mannheim, University of Heidelberg) approved the study. Informed consent was obtained in written form from all subjects. For the subjects’ characteristics, see Table 1. The visual stimulus for both fMRI and fTCD examination was a vertically rotating optokinetic drum with complex colored comic figures, as described in previous studies.[3, 20] Subjects were instructed to look at and pursuit the moving images on the drum revolving 10 times per minute. Functional TCD and MRI measurements were find more conducted consecutively in the same session. As first examination, we performed

the trans-temporal TCD recording from the P2 segments of both posterior cerebral arteries (PCA) simultaneously with a four-channel TCD scanner (DWL Multidop X, Compumedics Germany GmbH, Singen, Germany) with 2-MHz pulsed-wave Doppler 上海皓元医药股份有限公司 transducers affixed to a headband during visual stimulation with 10 averaged cycles of a 20-second “on” phase followed by a 20-second “off” phase (eyes closed). During the subsequent fMRI measurement, the stimulus was presented as a movie with the use of the “integrated functional imaging system” (Invivo, Orlando, FL, USA) via a liquid crystal display screen attached to the MRI head coil (see Fig. 1 —). Subjects with visual impairment were provided with MR-compatible corrective lenses. The MR scan was performed on a 1.5-T whole body scanner (Magnetom Sonata, Siemens Medical, Erlangen, Germany). A three-dimensional T1w whole brain data set was acquired (magnetization-prepared rapid gradient echo imaging; repetition time [TR]/echo time [TE]/flip angle/field of view [FOV] = 1.800 milliseconds/3.33 milliseconds/8°/240 mm) for anatomical reference with a voxel size of 1.3 × 1.3 × 1.2 mm3.

Methods:  A total of 247 patients who developed lamivudine-resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add-on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging

modalities every 3−6 months. Results:  HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase http://www.selleckchem.com/products/icg-001.html and α-fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan-Meier analysis, AST levels ≥ 70 IU/L, YIDD

mutants, cirrhosis and age ≥ 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion:  HCC can develop in cirrhotic patients receiving adefovir add-on lamivudine. Hence, Opaganib ic50 the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC. “
“Several major forces converged to catalyze the formal emergence of a body of knowledge and an organized focus on disorders of the liver in early life. Attendant to the development of a focused clinical subspecialty the pace of patient- and laboratory-based research in the field quickened in parallel to decipher the consequences of genetic or metabolic aberrations on immature liver structure and function. The key research observations that catalyzed the emergence and subsequent rapid growth of Pediatric Hepatology include: (1) an understanding of the dynamic events occurring during hepatobiliary development and the importance of these physiologic variables that occur during

liver maturation; (2) the recognition of the unique nature of inherited and acquired liver diseases that affect infants and children—such MCE as biliary atresia and Reye’s syndrome; and (3) redefinition of the once obscure inherited intrahepatic cholestatic diseases of the liver, which, in turn, provided insight into normal and abnormal hepatobiliary physiology. The clinical advances were highlighted by the development of specific approaches to the diagnosis and management of liver disease in infants and children, including both liver transplantation and nontransplant treatment options. These seminal events led to the expansion of the workforce, creating a critical mass consisting of individuals with focused, specialized skills and techniques.