05), IFNγ- (P < 0.01), and IL-17- (P < 0.05) and -4-producing CD4+ cells (P < 0.01) in Gal-3−/−, when compared buy Y-27632 to WT, mice 8 hours after Con A injection (Fig. 3). Furthermore, the total number of IL-12-producing CD11c+ DCs as well as IFNγ- and IL-4-producing NKT cells were significantly lower (P < 0.05) in livers of Gal-3−/−, when compared to WT, mice (Fig. 4). There was no significant difference in the total number of IFNγ-producing CD8+ T and NK cells and IL-10-producing CD11c+ DCs (data

not shown) between WT and Gal-3−/− mice. Interestingly, the total number of IL-10-producing CD4+ T cells and F4/80+ macrophages was significantly higher (P < 0.05) in livers of Gal-3−/−, compared to WT, mice (Figs. 3 and 5). Additionally, the ratio between the total number of IL-10- and IFNγ-producing CD4+ T cells was significantly higher (P < 0.05) in livers of Con A–treated Gal-3−/−, compared to WT, mice (4.53 ± 0.74 Gal3−/− versus 2.35 ± 0.56 WT). We did not find any difference in the total number of liver F4/80+ macrophages between WT and Gal-3−/−

mice, but we noticed a significant difference in the total number of IL-10-producing F4/80+ cells (Fig. 5A). We found a significantly higher percentage and total number of F4/80+ CD206+ alternatively activated (i.e., M2-polarized) macrophages in livers of Gal-3−/−, compared to WT, mice (Fig. 5A). Thus, it appears that Gal-3 deletion favors the differentiation of IL-10-producing macrophages. Talazoparib nmr We assumed that apoptosis of infiltrating cells may contribute to the lower number of MNCs in livers of Gal-3−/− mice. Indeed, we found enhanced apoptosis of liver-infiltrating MNCs and splenocytes in Gal-3−/−,

compared to WT, mice (Fig. 5B; Supporting Fig. 5) 8 hours after Con A injection. Both in livers and spleens, the majority of MNCs were in the stage MCE of late apoptosis (Annexin V+ propidium iodide [PI]+ cells; Fig. 5B; Supporting Fig. 5). Significantly higher percentages of Annexin V+ PI+ liver-infiltrating MNCs (P < 0.05) and splenocytes (P < 0.05) were observed in Gal-3−/−, mice compared to WT, mice (percentage of apoptotic cells in liver: 34% Gal3−/− versus 18.8% WT; in spleen: 38.7% Gal3−/− versus 17.3% WT). To further elucidate the role of Gal-3 in Con A–induced liver injury, we pretreated WT C57BL/6 mice with TD139, competing for the saccharide-binding site, 2 hours before and immediately after Con A injection. We found that the administration of TD139 prevented the increase of serum liver transaminases (Fig. 6A). This finding was consistent with scarce necrotic areas observed in the livers of pretreated animals, in contrast to significantly larger necrotic areas in liver parenchyma of mice treated with Con A and vehicle (Fig. 6B). IP injection of TD139 in Con A–untreated animals did not alter the serum level of liver enzymes (data not shown).

, 2013). Moreover, the high nest reuse in the same nest and the low nest alternation observed for both species would also explain this nest reuse pattern in territorial reoccupancies. Although other species maintain multiple nests to reinforce the territory, for example with an average of 6.9 nests per territory in golden eagles Aquila chrysaetos (Kochert & Steenhof, 2012), our species had few nests per territory (1.6 nests on average) mostly formed by one nest (50.75%). This prevalence of nest reuse in our study area underlines the importance of preserving old nests. Nest construction involves a considerable investment

of time and energy that could be reallocated directly to reproduction if nests were reused, possibly resulting in larger clutch sizes (Redmond et al., 2007) or in earlier clutch initiation (Cavitt et al., 1999). Nest building effort is even JNK inhibitor greater in some raptors, since each pair maintains or builds several nests and uses different nests in different years (up to 10 nests per pair in some cases; Fernández & Azkona, 1993; Ontiveros et al., 2008; Kochert & Steenhof, 2012) so breeding success could be limited by the availability of nesting sites. Our findings did not support the hypothesis that building a nest has a cost in reproductive output, and both booted eagle and common buzzard pairs clearly benefited from nest reuse buy CX-5461 by having a high

probability of breeding success, or more fledglings. In agreement with these results, nest building does not influence reproductive output by tree swallows Tachycineta bicolour (Rendell & Verbeek, 1996). In most papers reviewed by Mazgajski (2007), the presence of old nest holes did not influence breeding parameters. Nevertheless, the effects of nest building on reproductive output had different trends in new establishments and reoccupancy events. Newly established booted eagle pairs had a probability of breeding success and productivity

significantly higher when they built new nests than when they reused nests. Newly established common buzzards followed the same tendency with a higher probability of breeding success than booted 上海皓元 eagles (71.43 vs. 58.33%), since common buzzards are sedentary, avoiding the time and energetic costs involved in migration. Another study in the area concluded that territory quality was not relevant in the breeding success of booted eagle (Pagán et al., 2009), so we suggest that this effect on reproductive output could be due to booted eagle pairs having high individual quality, which they invest both in the building of new nest and breeding performance. These more successful newly established pairs tend to build nests, especially in new territories, and they are likely to be experienced individuals which do not follow territorial fidelity after breeding success the previous year (∼ 30% by booted eagles; Jiménez-Franco et al., 2013).

This is particularly the case for those patients who have failed

ITI. In many such patients, there is a need for prophylaxis with bypassing agents. Two bypassing agents are currently available: NovoSeven® [recombinant factor VIIa (rFVIIa); NovoNordisk, Bagsvaerd, Denmark]; and FEIBA® (FVIII inhibitor bypassing activity; Baxter AG, Vienna, Austria), a plasma-derived activated prothrombin complex concentrate (aPCC) [1,5,7,8]. These bypassing agents circumvent the usual coagulation process in which FVIII and FIX are integral to generate a blood clot [9]. These agents are used to treat bleeds in patients with high-responding inhibitors where traditional factor replacement is unlikely to be effective [7]. For patients with low-responding inhibitors (with a Bethesda titre <5 BU mL−1) [10,11], high doses of the replacement factor in which they

are deficient may be enough high throughput screening to resolve a bleed. The aim of this paper is to review and discuss current data for prophylaxis options for patients with haemophilia and inhibitors, with a particular emphasis on aPCC and rFVIIa, and to highlight upcoming studies investigating AZD1208 manufacturer bypassing agents for prophylaxis. Immune tolerance induction remains the only proven method of eradicating inhibitors in patients with high titre and high-responding (anamnestic) inhibitors [12]. Regimens for ITI therapy consist of regular infusions of replacement factor, with the aim of inducing antigen-specific tolerance that allows patients to re-institute conventional prophylaxis (factor replacement therapy) [13]. Data from international, German, Spanish and North American registries have led to a consensus amongst haemophilia opinion leaders that initiation of ITI therapy should generally be deferred until the inhibitor titre has decreased to below 10 BU mL−1, although this may delay treatment for 3–6 months. The benefit of waiting for the inhibitor titre to decrease may be negated if this MCE delay is in excess of 1–2 years [7]. During this period, inhibitor antibody levels should

be monitored closely to ensure timely initiation of ITI after the inhibitor titres have fallen sufficiently [7]. Immune tolerance induction is associated with adverse side effects related to the factor concentrate used (FVIII or FIX), the type and quantity of bypassing agent employed, any immunosuppressive agent (e.g. cyclophosphamide) administered and most frequently, the use of central venous access devices (CVADs) [14,15]. High doses of FVIII or FIX for ITI therapy (e.g. 200 U kg−1 day−1) raise the risk of thromboses development, particularly in patients who are also being administered high doses of bypassing agents to control or prevent bleeding [14]. Moreover, administration via a CVAD heightens the risk of thrombotic events in addition to the risk of infections associated with these devices [14,16].

This is particularly the case for those patients who have failed

ITI. In many such patients, there is a need for prophylaxis with bypassing agents. Two bypassing agents are currently available: NovoSeven® [recombinant factor VIIa (rFVIIa); NovoNordisk, Bagsvaerd, Denmark]; and FEIBA® (FVIII inhibitor bypassing activity; Baxter AG, Vienna, Austria), a plasma-derived activated prothrombin complex concentrate (aPCC) [1,5,7,8]. These bypassing agents circumvent the usual coagulation process in which FVIII and FIX are integral to generate a blood clot [9]. These agents are used to treat bleeds in patients with high-responding inhibitors where traditional factor replacement is unlikely to be effective [7]. For patients with low-responding inhibitors (with a Bethesda titre <5 BU mL−1) [10,11], high doses of the replacement factor in which they

are deficient may be enough AZD2014 cell line to resolve a bleed. The aim of this paper is to review and discuss current data for prophylaxis options for patients with haemophilia and inhibitors, with a particular emphasis on aPCC and rFVIIa, and to highlight upcoming studies investigating Trametinib chemical structure bypassing agents for prophylaxis. Immune tolerance induction remains the only proven method of eradicating inhibitors in patients with high titre and high-responding (anamnestic) inhibitors [12]. Regimens for ITI therapy consist of regular infusions of replacement factor, with the aim of inducing antigen-specific tolerance that allows patients to re-institute conventional prophylaxis (factor replacement therapy) [13]. Data from international, German, Spanish and North American registries have led to a consensus amongst haemophilia opinion leaders that initiation of ITI therapy should generally be deferred until the inhibitor titre has decreased to below 10 BU mL−1, although this may delay treatment for 3–6 months. The benefit of waiting for the inhibitor titre to decrease may be negated if this medchemexpress delay is in excess of 1–2 years [7]. During this period, inhibitor antibody levels should

be monitored closely to ensure timely initiation of ITI after the inhibitor titres have fallen sufficiently [7]. Immune tolerance induction is associated with adverse side effects related to the factor concentrate used (FVIII or FIX), the type and quantity of bypassing agent employed, any immunosuppressive agent (e.g. cyclophosphamide) administered and most frequently, the use of central venous access devices (CVADs) [14,15]. High doses of FVIII or FIX for ITI therapy (e.g. 200 U kg−1 day−1) raise the risk of thromboses development, particularly in patients who are also being administered high doses of bypassing agents to control or prevent bleeding [14]. Moreover, administration via a CVAD heightens the risk of thrombotic events in addition to the risk of infections associated with these devices [14,16].

13 How this is related to the autophagic stress that we describe herein is not fully known, but we can speculate that both phenomena are associated. Importantly, pharmacological inhibition of autophagy enhances the proapoptotic action of EFV. A complex relationship between autophagy and apoptosis has been suggested for several xenobiotics that induced both processes (imiquimod in basal cell carcinoma31 or oridonin in HeLa cells32) and, of note, in both cases the inhibition of autophagy promoted apoptosis which is in keeping with our results. Our understanding

of the role of autophagy in liver pathophysiology, especially regarding drug-induced hepatotoxicity, is limited.33, 34 However, sequestration of several subcellular compartments has been documented in hepatocytes under Talazoparib datasheet different conditions. Autophagy may play a role in three important aspects of hepatic physiopathology: organelle turnover, balance of nutrients and energy, and removal of misfolded/damaged proteins,33 and has been recently implicated in conditions such as liver ischemia-reperfusion injury, alcohol-related liver damage, hepatitis B/C infection, hepatocellular carcinoma, and nonalcoholic

liver disease.33, 34 Interestingly, hepatocytes were an early model for mitophagy following MPT and loss of ΔΨm. Recent data suggest that autophagy facilitates cell survival in various conditions of liver injury, including drug toxicity34; mitophagy was found to reduce hepatotoxicity and steatosis associated with

buy Ceritinib acute ethanol exposure,35 confer resistance to injury from menadione-induced oxidative stress,36 and promote survival of HepG2 cells against ginsenoside Rk1-induced apoptosis.37 Failure of this adaptive mechanism may lead to autophagic cell death. Our results add weight to this hypothesis, because 上海皓元医药股份有限公司 the mitochondrial degradation detected in our model occurs as a rescue mechanism that promotes hepatic cell survival, as shown by the fact that its pharmacological inhibition leads to increased EFV-induced cell damage. Nevertheless, when a massive autophagic response is induced the degradation capacity of the cell is exceeded, and “autophagic stress” is produced. Finally, there is growing evidence of a complex role of autophagy in viral infections including HIV38 and HBV/HCV,34 which is of special relevance in the light of our results. Hepatitis coinfections are very common among HIV patients and greatly enhance the hepatic toxicity of EFV.1, 2 In addition, there is evidence of autophagy induced by several protease inhibitors.39, 40, 41 Moreover, HIV patients usually receive concurrent medications that may be potentially hepatotoxic.1 All of this provides a picture of autophagic signaling/induction in which complex interactions take place between EFV and concomitant conditions which may ultimately influence liver function.

13 How this is related to the autophagic stress that we describe herein is not fully known, but we can speculate that both phenomena are associated. Importantly, pharmacological inhibition of autophagy enhances the proapoptotic action of EFV. A complex relationship between autophagy and apoptosis has been suggested for several xenobiotics that induced both processes (imiquimod in basal cell carcinoma31 or oridonin in HeLa cells32) and, of note, in both cases the inhibition of autophagy promoted apoptosis which is in keeping with our results. Our understanding

of the role of autophagy in liver pathophysiology, especially regarding drug-induced hepatotoxicity, is limited.33, 34 However, sequestration of several subcellular compartments has been documented in hepatocytes under Erlotinib cell line different conditions. Autophagy may play a role in three important aspects of hepatic physiopathology: organelle turnover, balance of nutrients and energy, and removal of misfolded/damaged proteins,33 and has been recently implicated in conditions such as liver ischemia-reperfusion injury, alcohol-related liver damage, hepatitis B/C infection, hepatocellular carcinoma, and nonalcoholic

liver disease.33, 34 Interestingly, hepatocytes were an early model for mitophagy following MPT and loss of ΔΨm. Recent data suggest that autophagy facilitates cell survival in various conditions of liver injury, including drug toxicity34; mitophagy was found to reduce hepatotoxicity and steatosis associated with

MK0683 price acute ethanol exposure,35 confer resistance to injury from menadione-induced oxidative stress,36 and promote survival of HepG2 cells against ginsenoside Rk1-induced apoptosis.37 Failure of this adaptive mechanism may lead to autophagic cell death. Our results add weight to this hypothesis, because medchemexpress the mitochondrial degradation detected in our model occurs as a rescue mechanism that promotes hepatic cell survival, as shown by the fact that its pharmacological inhibition leads to increased EFV-induced cell damage. Nevertheless, when a massive autophagic response is induced the degradation capacity of the cell is exceeded, and “autophagic stress” is produced. Finally, there is growing evidence of a complex role of autophagy in viral infections including HIV38 and HBV/HCV,34 which is of special relevance in the light of our results. Hepatitis coinfections are very common among HIV patients and greatly enhance the hepatic toxicity of EFV.1, 2 In addition, there is evidence of autophagy induced by several protease inhibitors.39, 40, 41 Moreover, HIV patients usually receive concurrent medications that may be potentially hepatotoxic.1 All of this provides a picture of autophagic signaling/induction in which complex interactions take place between EFV and concomitant conditions which may ultimately influence liver function.

Enrollment criteria included the following: 26 to 73 (median: 55) years of age; baseline serum HCV-RNA quantified by RT-PCR between 3.9 and 7.4 log copies/ml; and infection with HCV genotype 1 (n = 68) or 2 (n = 71). All patients (98 males and 41 females) were treated with pegylated Selleckchem BGB324 (PEG)-IFN alpha-2a alone, or PEG-IFN alpha-2a or PEG-IFN alpha-2b in combination with ribavirin. A negative result for serum HCV-RNA on RT-PCRat the assessment

point was defined as sustained virological response (SVR). Serum BTR, BCAA and Tyr were determined both at baseline and at the assessment point. Of 139 patients, 121 underwent liver biopsy before starting therapy, and the tissue specimens obtained were graded according to the Histology Activity Index (HAI) of Knodell et al. Specimens buy BVD-523 were also divided into four groups from stages 1 to 4 based on Desmet’s fibrosis scores. Of 139 patients, 51 consented to genetic investigation for polymorphisms in the interleukin (IL)-28B gene at rs8099917. Results: Serum BTR tended to decrease and serum Tyr tended to increase with grade or stage. Additionally,

49 of 68 CHC patients infected with genotype 1 and 66 of 71 CHC patients infected with genotype 2 showed SVR. In SVR patients, serum BTR was significantly. Conclusion: This study showed that, if HCV was eradicated from the liver in CHC patients infected with genotypes 1 and 2, BTR increased with reductions in serum Tyr levels. Key Word(s): 1. chronic hepatitis

C; 2. BTR Presenting Author: WON SOHN Additional Authors: YONG HAN PAIK, DONG HYUN SINN, GEUM YOUN GWAK, MOON SEOK CHOI, JOON HYEOK LEE, KWANG CHEOL KOH, SEUNG WOON PAIK, BYUNG CHUL YOO Corresponding Author: WON SOHN Affiliations: Samsung Medical Center, Samsung Medical Center, Samsung Medical Center, Samsung Medical Center, Samsung Medical Center, Samsung Medical Center, Samsung Medical Center, Samsung Medical Center Objective: Recent studies have shown that antiviral therapy may reduce the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV). This study was aimed to investigate the effect of virologic response to MCE公司 anti-viral therapy on the recurrence after curative resection in patients with HBV-related HCC. Methods: Between January 2008 and December 2010, a total of 72 antiviral therapy naïve patients underwent curative resection for HBV-related HCC (single nodule; <5 cm in diameter, or multi-nodule; number ≤3 and diameter <3 cm). All patients were treated with antiviral therapy within 1 month after resection (entecavir, 58; clevudine, 11; lamivudine, 3 patients). We assessed the risk factors for recurrence of HCC after curative resection. Complete virologic response to anti-viral therapy was defined as undetectable HBV DNA (9 IU/mL). Results: The median follow-up duration was 41.7 months.

αGalCer, alpha-galactosylceramide; α-SMA, alpha-smooth muscle actin; ctgf, connective tissue growth factor; FACS, fluorescent activated cell sorting; FFPE, formalin-fixed paraffin-embedded;

Foxf1, Forkhead box F1; Gli, glioblastoma; Hh, Hedgehog; HSC, hepatic stellate cells; iNKT, invariant natural killer T; LMNC, liver mononuclear cell; MCD, GDC0068 methionine choline deficient; mmp9, matrix metalloproteinase 9; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NK, natural killer; NKT, natural killer T; Ptc+/−, patched; Shh, sonic hedgehog; Tgf-β, transforming growth factor beta; Vcam1, vascular cell adhesion molecule 1. C57BL/6 wildtype (WT) (Jackson Laboratories, Bar Harbor, ME), Patched-deficient (Ptc+/−) mice (from R.J. Wechsler-Reya, Duke University, NC), and CD1d-deficient mice (from Z.P. Li, Johns Hopkins University, Baltimore, MD) were fed a methionine-choline deficient (MCD) diet or control chow for 8 weeks. Ptc+/−

mice have only one copy of patched, a Hedgehog (Hh)-pathway repressor. Therefore, they are unable to silence Hh-signaling and exhibit excessive Hh-pathway activity.25 NKT cells are genetically absent in CD1d-deficient mice.26 Formalin-fixed paraffin-embedded (FFPE)-livers were analyzed27 (for detailed protocol and antibodies, see Supporting Information Materials and Methods). Total liver RNA extraction

and messenger RNA (mRNA) quantification by real-time qualitative reverse-transcription polymerase chain reaction (qRT-PCR) were performed as detailed in Supporting Information selleck products Materials and Methods.27 Primers are in Supporting Information Table 1. Hydroxylproline content in whole liver specimens was quantified colorimetrically.27 LMNC were isolated from WT mice28, 29 MCE公司 and characterized by fluorescent antibody cell sorting (FACS) as detailed in Supporting Information Materials and Methods. LMNC were cultured in complete NKT media (RPMI 1640, supplemented with IL2 [10 ng/mL; Biolegend] and 10% heat-inactivated fetal bovine serum),28 with or without the NKT cell ligand, alpha-galactosylceramide (αGalCer; 100 ng/mL; Axxora, Cat. no. 306027, CA), for 24 hours. This αGalCer dose elicits maximal iNKT activation.30 Conditioned media were then added to primary murine HSCs for 1 day and RNA was harvested for qRT-PCR. Experiments were performed in duplicate wells and repeated twice. Murine cholangiocyte 603B line (from Yoshiyuki Ueno, Tohoku University, Sendai, Japan, and G. Gores, Mayo Clinic, Rochester, MN),31 rat HSC line 8B (from M. Rojkind, George Washington University, Washington, DC),32 and murine invariant hybridoma cell line DN32 (from Albert Bendelac, University of Chicago, Chicago, IL)33 were cultured according to established protocols.

αGalCer, alpha-galactosylceramide; α-SMA, alpha-smooth muscle actin; ctgf, connective tissue growth factor; FACS, fluorescent activated cell sorting; FFPE, formalin-fixed paraffin-embedded;

Foxf1, Forkhead box F1; Gli, glioblastoma; Hh, Hedgehog; HSC, hepatic stellate cells; iNKT, invariant natural killer T; LMNC, liver mononuclear cell; MCD, RAD001 methionine choline deficient; mmp9, matrix metalloproteinase 9; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NK, natural killer; NKT, natural killer T; Ptc+/−, patched; Shh, sonic hedgehog; Tgf-β, transforming growth factor beta; Vcam1, vascular cell adhesion molecule 1. C57BL/6 wildtype (WT) (Jackson Laboratories, Bar Harbor, ME), Patched-deficient (Ptc+/−) mice (from R.J. Wechsler-Reya, Duke University, NC), and CD1d-deficient mice (from Z.P. Li, Johns Hopkins University, Baltimore, MD) were fed a methionine-choline deficient (MCD) diet or control chow for 8 weeks. Ptc+/−

mice have only one copy of patched, a Hedgehog (Hh)-pathway repressor. Therefore, they are unable to silence Hh-signaling and exhibit excessive Hh-pathway activity.25 NKT cells are genetically absent in CD1d-deficient mice.26 Formalin-fixed paraffin-embedded (FFPE)-livers were analyzed27 (for detailed protocol and antibodies, see Supporting Information Materials and Methods). Total liver RNA extraction

and messenger RNA (mRNA) quantification by real-time qualitative reverse-transcription polymerase chain reaction (qRT-PCR) were performed as detailed in Supporting Information PXD101 datasheet Materials and Methods.27 Primers are in Supporting Information Table 1. Hydroxylproline content in whole liver specimens was quantified colorimetrically.27 LMNC were isolated from WT mice28, 29 MCE and characterized by fluorescent antibody cell sorting (FACS) as detailed in Supporting Information Materials and Methods. LMNC were cultured in complete NKT media (RPMI 1640, supplemented with IL2 [10 ng/mL; Biolegend] and 10% heat-inactivated fetal bovine serum),28 with or without the NKT cell ligand, alpha-galactosylceramide (αGalCer; 100 ng/mL; Axxora, Cat. no. 306027, CA), for 24 hours. This αGalCer dose elicits maximal iNKT activation.30 Conditioned media were then added to primary murine HSCs for 1 day and RNA was harvested for qRT-PCR. Experiments were performed in duplicate wells and repeated twice. Murine cholangiocyte 603B line (from Yoshiyuki Ueno, Tohoku University, Sendai, Japan, and G. Gores, Mayo Clinic, Rochester, MN),31 rat HSC line 8B (from M. Rojkind, George Washington University, Washington, DC),32 and murine invariant hybridoma cell line DN32 (from Albert Bendelac, University of Chicago, Chicago, IL)33 were cultured according to established protocols.

10 Autoimmunity was an emerging and exciting frontier. The concept of Burnet that autoreactive cells could escape into the peripheral circulation as “forbidden clones”11-13 heralded an era of disease discovery and understanding, and autoimmune hepatitis was a product of this surge. Autoimmunity, however, was still a vague pathogenic mechanism; it was not an etiologic agent like a virus or a drug; and it

could not be measured in the clinic. The evolving requisites for autoimmunity, especially the requirement for the transfer of disease by antibodies or lymphocytes, were restrictive,14,15 and “autoimmune” vied with “idiopathic” as an apt descriptor for the MK-2206 supplier fledgling condition. The wobbly legs of autoimmune hepatitis would persist for at least 2 decades. Systemic lupus erythematosus almost swallowed it16 and drug-induced17 and virus-related18,19 conditions repeatedly threatened its PI3K Inhibitor Library cell assay legitimacy. The goals of this review are to illustrate the dynamics of successful clinical investigation in liver disease and to underscore the vital role of the clinician nonscientist in starting and completing the circle of care from bedside-to-bench-to-bedside. Autoimmune hepatitis will be the “illustrative model” by which to accomplish these goals, and I will be the typical “clinician nonscientist.” The script can be applied broadly and accommodate any

substitute model or actor. The principal components of this tutorial are indicated below, and they rely heavily of good fortune, good mentoring, appropriate goal identification, adherence to protocol, compulsive record keeping, personal resilience, and strong collaborations. CALD, chronic active liver disease; HBsAg, hepatitis B surface antigen; HLA, human leukocyte antigen; IAIHG, International Autoimmune Hepatitis medchemexpress Group; MELD, Model for End-Stage Liver Disease. From 1969 to 1972, I had the good fortune to interact with academic clinicians who had a keen interest in

the study of liver disease (Table 1). At the Philadelphia General Hospital, Geobel Marin advocated the principles of controlled clinical trial and “double-blinded” investigation as the bases for new knowledge in clinical medicine, and my first article comparing peritoneoscopy with unguided needle biopsy of the liver illustrated some of these principles.20 At the University of Pennsylvania, Roger Soloway had just returned from a fellowship at the Mayo Clinic, and he presented wonderful data derived from a now classic controlled clinical trial that described the natural history and treatment of “chronic active liver disease”.21 My commitment to the study of liver disease was established through these contacts in Philadelphia as was my desire to train at the Mayo Clinic. Fortunately, Bill Summerskill agreed to accommodate this desire. The military draft interrupted my transition to Mayo, but my assignment to the U.S.