“
“(Headache 2010;50:1164-1174) Introduction.— Cluster headaches (CH) are primary headaches marked by repeated short-lasting attacks of severe, unilateral head pain and associated autonomic symptoms. Despite aggressive management with medications, oxygen therapy, nerve blocks, as well as various lesioning and neurostimulation therapies, a number of patients are incapacitated and suffering. The sphenopalatine ganglion (SPG) has been implicated in the pathophysiology of CH and has been a target for blocks, lesioning, and other surgical approaches. For this reason, it was selected as a target for an acute neurostimulation Palbociclib study. Methods.— Six patients with refractory chronic CH were treated with short-term (up to

1 hour) electrical stimulation of the SPG during an acute CH. Headaches were spontaneously present at the time of stimulation or were triggered with agents known to trigger clusters headache in each patient. A standard percutaneous infrazygomatic approach was used to place a needle at the ipsilateral SPG in the pterygopalatine fossa under fluoroscopic guidance. Electrical CHIR 99021 stimulation was performed using a temporary stimulating electrode. Stimulation was performed at various settings during maximal headache intensity. Results.— Five patients had CH during the initial evaluation. Three returned 3 months later for a second evaluation. There were 18 acute and distinct CH attacks

with clinically maximal visual analog scale (VAS) intensity of 8 (out of 10) and above. SPG stimulation resulted in complete resolution of the headache in 11 attacks, partial resolution (>50% VAS reduction) in 3, and minimal to no relief in 4 attacks. Associated autonomic Morin Hydrate features

of CH were resolved in each responder. Pain relief was noted within several minutes of stimulation. Conclusion.— Sphenopalatine ganglion stimulation can be effective in relieving acute severe CH pain and associated autonomic features. Chronic long-term outcome studies are needed to determine the utility of SPG stimulation for management and prevention of CH. “
“Serotonin (5-hydroxytryptamine)1B/1D agonists are vasoconstrictors that can affect coronary and cerebral arteries. Retrosternal chest, arm, and jaw pain following triptan use is generally attributed to “triptan sensations” and dismissed as noncardiac. However, triptans narrow normal coronary arteries and occasionally trigger vasospasm. They are contraindicated in atherosclerotic vascular disease. Part 1 of this review examines the relationship of medications used in migraine with the likelihood of causing vasospasm or vasoconstriction, and the triggering of cardiac arrhythmias. We report an illustrative case of polymorphic ventricular tachyarrhythmia, electrocardiogram changes consistent with cardiac ischemia, and acquired corrected QT interval lengthening following oral sumatriptan in a 53-year-old migraineur without risk factors for coronary artery disease (CAD).

Lastly, different types of extended half-life technology have been evaluated, with a focus on the practicalities and challenges associated with these products. Overall, the 4th Haemophilia Global Summit was a resounding success and provided delegates across the globe with the opportunity to interact www.selleckchem.com/products/ch5424802.html with an esteemed faculty and to learn and share experiences in the management

of haemophilia throughout all stages of life. I wish to thank my colleagues on the Scientific Steering Committee for a very educational and rewarding experience in the discussions and delivery of this programme. On behalf of the Committee, I would also like to give special thanks to Kelly McCauley and her team from Synergy who provided invaluable help and guidance to the Committee. Finally, on

behalf of the Committee and the delegates, I wish to acknowledge the unrestricted support from Pfizer and thank, in particular, Martina Westfeld and Brian Colvin for the real contribution that these Global Summits make to the educational aspects of global haemophilia care. Publication of this supplement was supported by an unrestricted educational grant from Pfizer. Dolan G. has received honoraria for speaking or advisory boards from Pfizer, Baxter, Bayer, Biotest, CSL, Grifols, Novo Nordisk and Octapharma. “
“Summary.  The laboratory has a key role in the initial detection of factor inhibitors and an ongoing role in the measurement of inhibitor titres during the course of inhibitor eradication therapy. The most commonly seen factor inhibitors are those directed against factor www.selleckchem.com/products/pexidartinib-plx3397.html VIII (FVIII), usually detected either using the original or Nijmegen-modified Bethesda assay. In view of previously demonstrated high variability in laboratory results for inhibitor assays, we have more extensively examined laboratory performance in the identification of FVIII inhibitors. Over the past 3 years, we conducted two questionnaire-based surveys and two wet-challenge surveys utilizing eight samples comprising no FVIII inhibitor (n = 1), or

low-titre (n = 2), medium-titre (n = 3) or high-titre (n = 2) FVIII inhibitor. Four samples were tested Abiraterone clinical trial by 42 laboratories in 2007, and four by 52 laboratories in 2009. High inter-laboratory variation was evident, with CVs around 50% not uncommon, and some 10% of all laboratories (or around 15% of laboratories using Bethesda method) failed to detect low-level inhibitors of around 1 BU mL−1. Laboratories using the Nijmegen method appeared to perform better than those using a standard Bethesda assay, with lower evident assay variation and no false negatives. There was a wide variety of laboratory practice, with no two laboratories using exactly the same process for testing and interpretation of factor inhibitor findings.

Lastly, different types of extended half-life technology have been evaluated, with a focus on the practicalities and challenges associated with these products. Overall, the 4th Haemophilia Global Summit was a resounding success and provided delegates across the globe with the opportunity to interact BGJ398 purchase with an esteemed faculty and to learn and share experiences in the management

of haemophilia throughout all stages of life. I wish to thank my colleagues on the Scientific Steering Committee for a very educational and rewarding experience in the discussions and delivery of this programme. On behalf of the Committee, I would also like to give special thanks to Kelly McCauley and her team from Synergy who provided invaluable help and guidance to the Committee. Finally, on

behalf of the Committee and the delegates, I wish to acknowledge the unrestricted support from Pfizer and thank, in particular, Martina Westfeld and Brian Colvin for the real contribution that these Global Summits make to the educational aspects of global haemophilia care. Publication of this supplement was supported by an unrestricted educational grant from Pfizer. Dolan G. has received honoraria for speaking or advisory boards from Pfizer, Baxter, Bayer, Biotest, CSL, Grifols, Novo Nordisk and Octapharma. “
“Summary.  The laboratory has a key role in the initial detection of factor inhibitors and an ongoing role in the measurement of inhibitor titres during the course of inhibitor eradication therapy. The most commonly seen factor inhibitors are those directed against factor this website VIII (FVIII), usually detected either using the original or Nijmegen-modified Bethesda assay. In view of previously demonstrated high variability in laboratory results for inhibitor assays, we have more extensively examined laboratory performance in the identification of FVIII inhibitors. Over the past 3 years, we conducted two questionnaire-based surveys and two wet-challenge surveys utilizing eight samples comprising no FVIII inhibitor (n = 1), or

low-titre (n = 2), medium-titre (n = 3) or high-titre (n = 2) FVIII inhibitor. Four samples were tested Bumetanide by 42 laboratories in 2007, and four by 52 laboratories in 2009. High inter-laboratory variation was evident, with CVs around 50% not uncommon, and some 10% of all laboratories (or around 15% of laboratories using Bethesda method) failed to detect low-level inhibitors of around 1 BU mL−1. Laboratories using the Nijmegen method appeared to perform better than those using a standard Bethesda assay, with lower evident assay variation and no false negatives. There was a wide variety of laboratory practice, with no two laboratories using exactly the same process for testing and interpretation of factor inhibitor findings.

Lastly, different types of extended half-life technology have been evaluated, with a focus on the practicalities and challenges associated with these products. Overall, the 4th Haemophilia Global Summit was a resounding success and provided delegates across the globe with the opportunity to interact IWR-1 cell line with an esteemed faculty and to learn and share experiences in the management

of haemophilia throughout all stages of life. I wish to thank my colleagues on the Scientific Steering Committee for a very educational and rewarding experience in the discussions and delivery of this programme. On behalf of the Committee, I would also like to give special thanks to Kelly McCauley and her team from Synergy who provided invaluable help and guidance to the Committee. Finally, on

behalf of the Committee and the delegates, I wish to acknowledge the unrestricted support from Pfizer and thank, in particular, Martina Westfeld and Brian Colvin for the real contribution that these Global Summits make to the educational aspects of global haemophilia care. Publication of this supplement was supported by an unrestricted educational grant from Pfizer. Dolan G. has received honoraria for speaking or advisory boards from Pfizer, Baxter, Bayer, Biotest, CSL, Grifols, Novo Nordisk and Octapharma. “
“Summary.  The laboratory has a key role in the initial detection of factor inhibitors and an ongoing role in the measurement of inhibitor titres during the course of inhibitor eradication therapy. The most commonly seen factor inhibitors are those directed against factor www.selleckchem.com/products/Roscovitine.html VIII (FVIII), usually detected either using the original or Nijmegen-modified Bethesda assay. In view of previously demonstrated high variability in laboratory results for inhibitor assays, we have more extensively examined laboratory performance in the identification of FVIII inhibitors. Over the past 3 years, we conducted two questionnaire-based surveys and two wet-challenge surveys utilizing eight samples comprising no FVIII inhibitor (n = 1), or

low-titre (n = 2), medium-titre (n = 3) or high-titre (n = 2) FVIII inhibitor. Four samples were tested Epothilone B (EPO906, Patupilone) by 42 laboratories in 2007, and four by 52 laboratories in 2009. High inter-laboratory variation was evident, with CVs around 50% not uncommon, and some 10% of all laboratories (or around 15% of laboratories using Bethesda method) failed to detect low-level inhibitors of around 1 BU mL−1. Laboratories using the Nijmegen method appeared to perform better than those using a standard Bethesda assay, with lower evident assay variation and no false negatives. There was a wide variety of laboratory practice, with no two laboratories using exactly the same process for testing and interpretation of factor inhibitor findings.

A major concern in transplant recipients is the potential for toxicity from immunosuppressive drugs (tacrolimus, cyclosporine, sirolimus, and everolimus). All four immunosuppressants are metabolized by way of the hepatic enzyme, CYP3A, an enzyme that is inhibited by both telaprevir and boceprevir. Tacrolimus area under the curve (AUC) increases 70.3-fold and cyclosporine HKI-272 concentration AUC increases

4.6-fold when coadministered with telaprevir. Tacrolimus AUC increases 17.1-fold and cyclosporine AUC increases 2.7-fold when coadministered with boceprevir. What this means to transplant hepatologists and patients is obvious: When using TT, major reductions in doses of tacrolimus, cyclosporine, sirolimus, and everolimus are required to avoid toxicity and drug levels must be monitored closely. Also, when telaprevir or boceprevir are discontinued, doses of these immunosuppressants

must be increased and levels monitored to prevent rejection.[12] Telaprevir and boceprevir may also affect the metabolism of other medications, including antibiotics, sedatives, antipsychotics, statins, oral contraceptives, warfarin, proton-pump inhibitors, and others. A careful consideration of all potential DDIs is required before initiating TT.[12] Severe anemia has been a major management issue in treating patients after LT. Anemia during antiviral therapy is the result of the combination of hemolysis Selleck AZD6244 from RBV and bone marrow (BM) suppression from IFN and telaprevir or boceprevir. Hematopoiesis may be further compromised by immunosuppressive drugs. In our experience, hemoglobin drops by 1.5 g/dL during lead-in with PEG-RBV and by 2.5 g/dL in the first 1-4 weeks after the addition of telaprevir.[16] Anacetrapib Sixty-one percent (11 of 18) of our patients required erythropoietin (EPO); 6 of the 11 who required EPO were started during PEG-RBV lead-in. Eighty-three percent (15 of 18) had RBV dose reduction after the addition

of telaprevir. A majority (10 of 18) of patients required at least one blood transfusion, with most (8 of 10) of these transfusions being given during the telaprevir phase of the protocol. Of the 10 patients receiving blood transfusion, a total of 60 units of blood were transfused (48 units during the telaprevir phase of the protocol). This experience emphasizes that intervention for anemia is required early during TT, decreases in hemoglobin can be precipitous, and multiple approaches to control anemia may be needed simultaneously.[16] Curiously, rash events have been extremely rare in our transplant recipients. Rash has been reported in over 50% of nontransplant patients taking telaprevir-based TT, and 5%-7% of these patients have had to stop telaprevir because of severe rash. Only rare patients in our experience have had rash.

A major concern in transplant recipients is the potential for toxicity from immunosuppressive drugs (tacrolimus, cyclosporine, sirolimus, and everolimus). All four immunosuppressants are metabolized by way of the hepatic enzyme, CYP3A, an enzyme that is inhibited by both telaprevir and boceprevir. Tacrolimus area under the curve (AUC) increases 70.3-fold and cyclosporine Tyrosine Kinase Inhibitor Library datasheet AUC increases

4.6-fold when coadministered with telaprevir. Tacrolimus AUC increases 17.1-fold and cyclosporine AUC increases 2.7-fold when coadministered with boceprevir. What this means to transplant hepatologists and patients is obvious: When using TT, major reductions in doses of tacrolimus, cyclosporine, sirolimus, and everolimus are required to avoid toxicity and drug levels must be monitored closely. Also, when telaprevir or boceprevir are discontinued, doses of these immunosuppressants

must be increased and levels monitored to prevent rejection.[12] Telaprevir and boceprevir may also affect the metabolism of other medications, including antibiotics, sedatives, antipsychotics, statins, oral contraceptives, warfarin, proton-pump inhibitors, and others. A careful consideration of all potential DDIs is required before initiating TT.[12] Severe anemia has been a major management issue in treating patients after LT. Anemia during antiviral therapy is the result of the combination of hemolysis Alectinib nmr from RBV and bone marrow (BM) suppression from IFN and telaprevir or boceprevir. Hematopoiesis may be further compromised by immunosuppressive drugs. In our experience, hemoglobin drops by 1.5 g/dL during lead-in with PEG-RBV and by 2.5 g/dL in the first 1-4 weeks after the addition of telaprevir.[16] Inositol monophosphatase 1 Sixty-one percent (11 of 18) of our patients required erythropoietin (EPO); 6 of the 11 who required EPO were started during PEG-RBV lead-in. Eighty-three percent (15 of 18) had RBV dose reduction after the addition

of telaprevir. A majority (10 of 18) of patients required at least one blood transfusion, with most (8 of 10) of these transfusions being given during the telaprevir phase of the protocol. Of the 10 patients receiving blood transfusion, a total of 60 units of blood were transfused (48 units during the telaprevir phase of the protocol). This experience emphasizes that intervention for anemia is required early during TT, decreases in hemoglobin can be precipitous, and multiple approaches to control anemia may be needed simultaneously.[16] Curiously, rash events have been extremely rare in our transplant recipients. Rash has been reported in over 50% of nontransplant patients taking telaprevir-based TT, and 5%-7% of these patients have had to stop telaprevir because of severe rash. Only rare patients in our experience have had rash.

Very recently, it has been shown that genotoxic and ER stress can inhibit mTOR activity in

the liver through induction of Sestrin2.[19, 20] Here, a significantly stronger induction of Sestrin2 was evident in Fah/p21−/− mice 3 months after NTBC reduction (increase of 50%) (Fig. 5C), suggesting that loss of p21 leads to a compensatory activation of Sestrin2, which subsequently inhibits mTOR activity. Moreover, Sestrin2 has been shown to activate Nrf2 signaling in mouse livers by promoting p62-dependent autophagic degradation of Keap1.[20] Accordingly, microarray and reverse-transcriptase PCR analysis revealed a significant stronger activation of several known downstream targets genes of Nrf2 including HO-1, Nqo1, and GSTm4 in Z-IETD-FMK supplier livers of Fah/p21−/− mice compared with Fah−/− mice (Fig. 5D,E). Liver injury is often accompanied by severe DNA damage of hepatocytes, which leads to an activation of DNA repair pathways, including p53 and p21. Subsequent development of preneoplastic lesions and their progression to HCC reflects the convergence of genetic and epigenetic defects that provoke dysregulation of

pathways controlling cell cycle progression. Several previous studies have shown that p21 regulates liver regeneration and hepatocarcinogenesis. JNK1-dependent down-regulation of p21, for example, is required for proliferation of hepatocytes and tumor progression in chemically induced carcinogenesis.[3] Similarly, we confirmed our findings in Fah-deficient mice that http://www.selleck.co.jp/products/abt-199.html loss of p21 permits proliferation of hepatocytes with severe DNA damage, which SB203580 supplier rapidly progresses to dysplastic hepatocytes and HCC.[2] These studies established p21 as a negative regulator of hepatocyte proliferation and as a tumor suppressor. Paradoxically, however, we report here that hepatocyte proliferation was significantly reduced and, more importantly, tumor development was profoundly delayed in p21-deficient mice with moderate liver injury, providing further insight into the complex regulation of cellular processes required

for liver regeneration and tumor development. The late spontaneous tumor onset in p21-deficient mice and the rarity of p21 loss of function mutations in cancer already provided some evidence that p21 is not a classical tumor suppressor. Here, we provide evidence that loss of p21 may actually promote or delay tumor development in the same disease and the same organ depending on the degree of preexisting injury. Previous studies and our own observation suggest that the ability of p21 to modulate liver tumor development is closely linked to its ability to control cell cycle progression of hepatocytes. Interestingly, however, the role of p21 for liver regeneration appears to depend on the degree of liver injury and the strength of subsequent induction of p21.

Silymarin inhibition of MTP activity and apoB secretion correlated with a reduction in de novo virion production from fully infected cultures treated for 5 hours (Fig. 4C). Importantly, the reduction in infectious virus production was not attributable to a reduction in intracellular replication, because NS5A protein levels were not affected by the 5-hour treatments with DMSO, silymarin, CHIR-99021 supplier or BMS-200150 (Fig. 4D). Furthermore, the effect on apoB secretion was not unique to Huh7 cells, because silymarin also caused dose-dependent suppression of apoB secretion from primary human hepatocytes (Fig. 4E) and HepG2 cells, as measured by ELISA and western blot

(Fig. 4F). When we examined intracellular infectious virus as a measure of virus assembly, the general secretion inhibitor Brefeldin A caused accumulation of intracellular infectious virus, which was inhibited by the MTP inhibitor BMS-200150, as described by Gastaminza et al.20 However, silymarin had no effect on Brefeldin A-induced accumulation of infectious virus (Supporting Fig. S6). Collectively, the data demonstrate that silymarin blocks MTP-dependent apoB secretion and infectious virion production into culture supernatants, but does not appear to block virus assembly. We then determined

whether silymarin blocks other pathways of virus transmission. It has been recently shown that, in addition to releasing virus particles into culture medium, HCV is capable of direct cell-to-cell transmission.21 To examine effects of silymarin on this see more antibody-insensitive route of transmission, we used a novel assay in which fluorescently labeled infected producer cells were mixed with unlabeled naïve cells, and HCV NS5A protein expression was detected using antibodies

labeled in the red spectrum. Silymarin reduced both total and cell-to-cell transmission (Fig. 5A). We also observed equal suppression 4-Aminobutyrate aminotransferase of both total and cell-to-cell transmission (Fig. 5B), suggesting that silymarin does not discriminate between routes of virus transmission. Despite global use for millenia, the detailed molecular mechanisms of silymarin-induced hepatoprotection are not known. In recent studies,6, 31 we have shown that silymarin displays antiviral, anti-inflammatory, and immunomodulatory functions. These activities, together with antioxidant functions of silymarin,32 could effectively constitute the hepatoprotection observed in many animal models of liver disease.33-35 Using HCVpp, HCVcc, and liposome mixing experiments, we demonstrate that silymarin inhibits virus entry and fusion, RNA and protein synthesis, and infectious virus production into culture supernatants and cell-to-cell spread. Silymarin but not silibinin inhibited NS5B polymerase activity.

The HEV strain (HE-JA11-1701) isolated from the patient belonged to genotype 3 and European-type subgenotype 3e. It was presumed that the patient had been infected from a wild boar (Sus scrofa leucomystax) because he consumed meat/viscera from a wild boar that he had captured himself as a hunter approximately 2 months before disease

onset. A specimen of the boar meat/viscera that the patient had ingested was not available. However, the HE-JA11-1701 strain was 99.8% identical within the 412-nucleotide sequence of the open reading frame 2 region to a HEV strain (JBOAR012-Mie08) that had been recovered from a wild boar captured near the patient’s hunting area in 2008. A phylogenetic analysis confirmed that the two HEV strains had a close genetic relationship and were segregated into subgenotype 17-AAG datasheet 3e, supported by a high bootstrap value of 99%. Of note, the HE-JA11-1701 and JBOAR012-Mie08 strains were remotely

related to the 3e strains reported in Japan and European countries, with a nucleotide difference of 7.9–13.9%, reinforcing the uniqueness of the 3e strains obtained in the present study. These results strongly support our speculation that the patient developed acute hepatitis E via consumption of HEV-infected boar meat/viscera. Genetic analyses of HEV strains are useful for tracing infectious sources in sporadic cases of acute hepatitis E. “
“Aim:  The increasing prevalence of fatty liver disease requires routine assessment methods. selleck chemicals Proton magnetic resonance spectroscopy (1H MRS) is increasingly used for steatosis measurement, but due to cost, is unlikely to become a widely-used screening tool. Ultrasound is cheaper and more widely available, although subject to observer variability. Our aim was to determine the sensitivity and specificity

of ultrasound against 1H MRS, using MRS as a gold standard, for the detection and quantification of hepatic fat content. Methods:  Fifty adults participated (43 men, seven women) in this study. Hepatic steatosis was assessed by ultrasound and 1H MRS. Images were graded by two independent radiologists to classify severity and distribution of liver Thymidylate synthase fat. Results:  Ultrasound detected liver fat infiltration in 82% of cases measurable by 1H MRS, while liver fat was detectable in 44% of cases graded absent by ultrasound. Ultrasound grading was subjective, with the radiologists in agreement in 53% of cases (κ = 0.39, P = 0.002). Considerable overlap in intrahepatocellular lipid content was observed between different grades: absent (0.0–1.58%), mild (2.2–16.2%), moderate (4.9–26.7%) and severe (8.1–76.8%) steatosis. Ultrasound could not detect liver fat levels below 2% as measured by 1H MRS Conclusion:  Ultrasound is less sensitive than 1H MRS in detecting very low levels of liver fat content, but is sensitive to fatty infiltration greater than 2%.

Velasco, Guillermo Veldt, Bart Venook, Alan P. Vergani, Diego Vierling, John Vilgrain, Valérie Villamil, Federico Villanueva, Augusto Villunger, Andreas Vilstrup, Hendrik Vogel, Wolfgang Volk, Michael Volzke, Henry Vos, Miriam Vuppalanchi, Raj Wakita, Takaji Wald, Cristoph Walker, Christopher Walker, Neff Wan, Yu-Jui Wands, Jack Wang, Bruce Wang, David Wang, Fu-Sheng Wang, Li Wang, Tianyi Wang, Xin Wang, Yu Wang, Yue Wang, Yunfang Waters, Michael Watkins,

Paul Watt, Kymberly Webster, Cynthia R. L. Wedemeyer, Heiner Wee, Aileen Weigert, Cora Weinman, Steven Weinreb, Jeffrey Weissenborn, Karin Wells, Rebecca Wen, Li Wendon, Julia Weston, Shiobhan Whitington, Peter Wiesner, Russell wiest, reiner Wigmore, Stephen Willenbring, Holger Williams, Roger Wilson, Joyce wolin, sandra Wolkoff, Allan Wong, David Wong, Florence Worman, CYC202 Howard Wu, Tong Xian-Ming, Chen Xie, Wen Xu, Teng Yabe-Nishimura, DAPT Chihiro Yang, Hushan Yang, PY Yawn, Barbara Yeh, Matthew Yeomans, Neville Yeung, Latifa Yin, Xiao-Ming Yokoyama, Shinji Yoneda, Masato Yoshizato, Katsutoshi You, Min Young, Martin Younossi, Zobair Yu, Dae-Yeul Yu, Herbert Yuan,

Jian-Min Yuen, Man-Fung Zeilinger, Katrin Zein, Claudia Zen, Yoh Zender, Lars Zeniya, Mikio Zern, Mark Zhang, Xiao-kun Zheng, Limin zhu, qiang Zoller, Heinz Zollner, Gernot Zoulim, Fabien Zucman-Rossi, Jessica “
“Ectodomain shedding of tumor necrosis factor receptor 1 (TNFR1) provides negative feedback HA-1077 in vivo to the inflammatory loop induced by TNFα. As the significance of this mechanism in obesity-associated pathologies is unclear, we aimed to unravel how much TNFR1 ectodomain shedding controls

the development of nonalcoholic fatty liver disease (NAFLD), as well as its role in the development of insulin resistance. We used knockin mice expressing a mutated TNFR1 ectodomain (p55Δns), incapable of shedding and dampen the inflammatory response. Our data show that persistent TNFα signaling through this inability of TNFR1 ectodomain shedding contributes to chronic low-grade inflammation, which is confined to the liver. In spite of this, hepatic lipid levels were not affected by the nonshedding mutation in mice fed a chow diet, nor were they worse off following 12 weeks of high-fat diet (HFD) than controls (p55+/+) fed an HFD. We detected inflammatory infiltrates, hepatocellular necrosis, and apoptosis in livers of p55Δns/Δns mice fed an HFD, suggesting advanced progression of NAFLD toward nonalcoholic steatohepatitis (NASH). Indeed, fibrosis was present in p55Δns/Δns mice, but absent in wildtype mice, confirming that the p55Δns/Δns mice had a more severe NASH phenotype. Despite low-grade hepatic inflammation, insulin resistance was not observed in p55Δns/Δns mice fed a chow diet, and HFD-induced insulin resistance was no worse in p55Δns/Δns mice than p55+/+ mice. Conclusion: TNFR1 ectodomain shedding is not an essential feedback mechanism in preventing the development of hepatic steatosis or insulin resistance.