125, p < .001] indicating that patients with TLE surprisingly crossed a greater number of boxes than controls. The effect of condition failed to reach significance [F(1, 34) = 3.736, p > .062], the group and condition interaction was also not significant [F(1, 34) = 0.094, p > .761]. Notably, analysis of the proportional loss in performance from single- to dual-task conditions on the individual tasks failed to reveal a significant group difference for both the digit recall task [t(34) = .867, p > .392] and the tracking task [t(34) = .394, p > .696].

Indeed, the composite index of dual performance Z-VAD-FMK ic50 (μ) showed that the dual-task decrement was indeed almost identical between the two groups [t(34) = .229,

p > .782]. The mean scores and standard deviations for the additional measures of attention are displayed in Table 3. Differences between the participant groups on TEA-2 and TEA-3 were analysed LDK378 with t-tests. Scores on the remaining tests were entered into four further 2 × 2 ANOVAs that treated group as a between-subjects factor and condition of the respective tests as a within-subjects factor. Patients with TLE demonstrated impairments in digit span [F(1, 34) = 28.227, p < .0001], spatial span [F(1, 34) = 5.234, p < .028], the TMT [F(1, 34) = 11.836, p < .002], and the OMO test [F(1, 34) = 6.629, p < .015]. None of the group and condition interactions were significant. There was no significant difference in the number of correct responses on TEA-2 [t(34) = 1.694, p > .099], although control participants produced more correct responses on TEA-3 [t(34) = 4.779, p < .0001]. The aim of this

study was to extend what is known about attentional control in patients with TLE, by examining in a single cohort, the status of dual-task coordination together with performance on a range of more traditional measures of attentional control. We found that the proportional decrement in dual-task performance relative to single performance on each of the constituent tasks did not differ between the groups. Thus, indicating that TLE does not impact upon the ability to allocate cognitive resources. In contrast, consistent with previous studies (e.g., Piazzini et al., 2006), TLE patients displayed a deficit on medchemexpress TMT-A and disproportionate deficit on TMT-B, revealing a dissociation between dual-task performance and divided attention. Unlike the dual-task paradigm in TMT-B, the two sources of information are from the same modality and therefore the task is likely to be vulnerable to reduced processing capacity (cf. Lonie et al., 2009). It has indeed been posited that deficits in attentional control in TLE might only manifest on tasks where the demand characteristics are particularly high (McDonald et al., 2005) and the findings from this study appear consistent with this view.

All of the described experiments

were performed using male mice aged between 8 and 12 weeks. For quantitative real-time polymerase chain reaction (PCR) messenger RNA (mRNA) was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA) after complementary DNA synthesis expression was determined using the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA) (see Supporting Information for details). PD-1/PD-L1 inhibitor cancer For immunohistochemical analysis, paraffin-embedded tissue slides were stained using a primary anti-Glut2 antibody (1:150) (Abcam, Cambridge, MA) and fluorescence or horseradish peroxidase (HRP)-labeled secondary antibodies (Vectorstain ABC-Kit, Vector Laboratories, Burlingame, CA). Staining was detected using a Nikon light, or fluorescence microscope, respectively (see Supporting Information for details). Proteins were separated by way of sodium dodecyl sulfate–polyacrylamide gel electrophoresis and electrotransfered onto nitrocellulose membranes (Invitrogen, Carlsbad, CA), and protein expression was determined using the indicated primary antibodies (Supporting Table 1). Binding of the antibody was detected using HRP-labeled secondary antibodies (BioRad, Hercules, CA) and the Amersham ECL Plus Western Blotting Detection Reagents TSA HDAC solubility dmso (GE Healthcare, Baie d’Urfe, Quebec, Canada). Chemiluminescence was determined using a KODAK ImageStation

4000MM (Mandel, Guelph, Ontario, Canada). Animals were fed ad libitum using a western diet (TestDiet, Richmond, IN) containing 16.8% protein, 6.5% fiber, 48% carbohydrates, and 20% fat. After 6 weeks of feeding, wild-type and Slco1b2−/− mice were sacrificed and blood samples were collected. The measurement of cholesterol and MCE TSH was performed at Charles River Laboratories (Wilmington, MA). Total and free thyroxine (T4) and triiodothyronine (T3) in plasma were determined using enzyme-linked immunosorbent assay (ELISA) kits from Alpha-Diagnostics (San Antonio, TX). Insulin levels were determined using the UltraSensitive Mouse Insulin ELISA kit (Crystal

Chem Inc., Downers Grove, IL). Total bile acids or 7-α-hydroxy-4-cholesten-3-one were determined using a commercially available colorimetric assay (BioQuant, San Diego, CA) or mass spectrometry, respectively (see Supporting Information for details). Glucose tolerance testing and pyruvate challenge were performed using 2 g/kg glucose or pyruvate. Glucose levels were determined using a glucometer (OneTouch, LifeScan Inc., Milpitas, CA). For thyroid hormone (TH) extraction, tissue was homogenized in methanol. After addition of chloroform (2:1) and centrifugation (15 minutes, 1,900g, 4°C), pellets were re-extracted with a chloroform/methanol (2:1) mixture. Both supernatants were combined and further extracted with chloroform/methanol/water (8:4:3) and 0.05% CaCl2. The mixed solution was centrifuged (10 minutes, 800g, 4°C). Lower apolar phase was re-extracted with chloroform/methanol/water (3:49:48).

All of the described experiments

were performed using male mice aged between 8 and 12 weeks. For quantitative real-time polymerase chain reaction (PCR) messenger RNA (mRNA) was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA) after complementary DNA synthesis expression was determined using the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA) (see Supporting Information for details). RAD001 concentration For immunohistochemical analysis, paraffin-embedded tissue slides were stained using a primary anti-Glut2 antibody (1:150) (Abcam, Cambridge, MA) and fluorescence or horseradish peroxidase (HRP)-labeled secondary antibodies (Vectorstain ABC-Kit, Vector Laboratories, Burlingame, CA). Staining was detected using a Nikon light, or fluorescence microscope, respectively (see Supporting Information for details). Proteins were separated by way of sodium dodecyl sulfate–polyacrylamide gel electrophoresis and electrotransfered onto nitrocellulose membranes (Invitrogen, Carlsbad, CA), and protein expression was determined using the indicated primary antibodies (Supporting Table 1). Binding of the antibody was detected using HRP-labeled secondary antibodies (BioRad, Hercules, CA) and the Amersham ECL Plus Western Blotting Detection Reagents click here (GE Healthcare, Baie d’Urfe, Quebec, Canada). Chemiluminescence was determined using a KODAK ImageStation

4000MM (Mandel, Guelph, Ontario, Canada). Animals were fed ad libitum using a western diet (TestDiet, Richmond, IN) containing 16.8% protein, 6.5% fiber, 48% carbohydrates, and 20% fat. After 6 weeks of feeding, wild-type and Slco1b2−/− mice were sacrificed and blood samples were collected. The measurement of cholesterol and MCE公司 TSH was performed at Charles River Laboratories (Wilmington, MA). Total and free thyroxine (T4) and triiodothyronine (T3) in plasma were determined using enzyme-linked immunosorbent assay (ELISA) kits from Alpha-Diagnostics (San Antonio, TX). Insulin levels were determined using the UltraSensitive Mouse Insulin ELISA kit (Crystal

Chem Inc., Downers Grove, IL). Total bile acids or 7-α-hydroxy-4-cholesten-3-one were determined using a commercially available colorimetric assay (BioQuant, San Diego, CA) or mass spectrometry, respectively (see Supporting Information for details). Glucose tolerance testing and pyruvate challenge were performed using 2 g/kg glucose or pyruvate. Glucose levels were determined using a glucometer (OneTouch, LifeScan Inc., Milpitas, CA). For thyroid hormone (TH) extraction, tissue was homogenized in methanol. After addition of chloroform (2:1) and centrifugation (15 minutes, 1,900g, 4°C), pellets were re-extracted with a chloroform/methanol (2:1) mixture. Both supernatants were combined and further extracted with chloroform/methanol/water (8:4:3) and 0.05% CaCl2. The mixed solution was centrifuged (10 minutes, 800g, 4°C). Lower apolar phase was re-extracted with chloroform/methanol/water (3:49:48).

This initially suggested that undernutrition in early development induced permanent alterations in regulatory pathways during periods of developmental plasticity, ultimately HIF inhibitor resulting in adult disease.7

We and others have currently shown, unequivocally in animal models, that exposure to maternal obesity and overnutrition predisposes offspring to obesity and metabolic dysfunction in adulthood.8, 9 Programmed metabolic abnormalities arising from prenatal and/or early postnatal under- and overnutrition may then be amplified, in the context of postnatal overnutrition, to cause disruption of the adipoinsular axis as well as development of insulin resistance (IR) to promote hepatosteatosis.5 Indeed, there is some evidence, from studies of obese women, that the fetus may already be insulin resistant toward the end of gestation.10 Hepatosteatosis and IR are considered

to be the initiating factors in the pathophysiological cascade underpinning NAFLD, and the process is likely to be propagated by the adipokines, tumor necrosis factor alpha (TNF-α) and interleukin Cobimetinib (IL)-6,2 through generation of reactive oxygen species (ROS).11 The hepatic innate immune system is also implicated through inflammatory cytokines IL-12 and IL-18. In addition, destruction of Kupffer cells (KCs) using clodronate liposomes in a mouse model of NASH has been shown to blunt steatosis,12 and it has been proposed that KC-mediated cytokine production impairs lipid peroxidation and propagates IR, culminating in hepatosteatosis.13 Additionally, natural killer T (NKT) cells, potential mediators of an anti-inflammatory response, are selectively reduced in the ob/ob mouse model.14 The protocol in our earlier study,3 though demonstrating a role for maternal overnutrition in the pathogenesis of NAFLD, employed a cross-fostering strategy to delineate the relative role of the in

utero and suckling periods and therefore lacked some physiological MCE relevance. Indeed, we have subsequently shown that the process of offspring cross-fostering can, of itself, induce modest dysmetabolic changes in offspring.15 Therefore, our aim in the present study was to confirm the involvement of developmental programming in the pathogenesis of NAFLD and interrogate the responsible mechanisms using a pathophysiologically relevant murine model in which offspring of dams fed an obesogenic diet are themselves reared on the same diet. The diet, as reported on previously,3, 16 is a highly palatable, high-fat, high-sugar, energy-dense diet designed to mimic the Western diet associated with increased obesity risk.17 We show that offspring of obese dams weaned onto an obesogenic diet developed a more-robust dysmetabolic and NAFLD phenotype, with induction of fibrosis, compared to offspring of lean dams weaned onto the same obesogenic diet or a standard control diet.

It is striking that none of the 12 compounds without any

hepatic metabolism had any identifiable reports of liver failure, liver transplantation, or fatal DILI. This does not necessarily mean that compounds without hepatic metabolism are entirely immune from hepatotoxicity, but it is significantly less likely. One example of a drug in which selective hepatic metabolism did not cause serious hepatotoxicity is ximelagatran, which was not approved by the Food and Drug Administration due to cases of hepatotoxicity during ABT-263 order its development.9–10 Because this medication was never approved for clinical use in the United States, it was not included in our study. Another example is pregabalin, which is also without hepatic metabolism but may be rarely associated with suspected severe hepatotoxicity.20 Because it was approved in December 2004, it was not included in our brand name compound category. Thus, lack of hepatic metabolism does not assure total lack of hepatotoxicity, but based on our data it indeed appears to be quite rare. According to the pharmacological interaction hypothesis, some drugs may be able to initiate an immune response through a reversible interaction with the major histocompatibility complex–T cell receptor complex.21 It has been postulated that ximelagatran leads

to hepatotoxicity by evoking an immune response by binding directly but reversibly to major histocompatibility Belinostat concentration complex.10 Second, we did not find a significant relationship between the frequency of hepatic adverse events and whether a compound is

metabolized by phase I and/or phase II reactions. Compounds with only phase II metabolism were not immune from hepatic adverse events. If confirmed, these observations are important, because they argue against a singular role for reactive metabolites 上海皓元 generated by phase I reactions in causing hepatotoxicity. Third, we found a statistically significant relationship between reports of jaundice and whether a compound has biliary excretion. Although it was not always clear from the reports contained within the DRUGDEX whether jaundice is hepatocellular or cholestatic in nature, we found that it was cholestatic in a substantial proportion. This leads us to speculate that compounds with biliary excretion may cause cholestatic jaundice in genetically predisposed individuals (e.g., defective transporters). There is increasing evidence that cholestatic liver injury associated with certain compounds results from a drug- or metabolite-mediated inhibition of hepatobiliary transport systems.22 Furthermore, we observed an additive effect of daily dose and hepatic metabolism; oral compounds with significant hepatic metabolism but also given at daily doses ≥50 mg had the highest risk of hepatic adverse drug reactions compared with other groups (Table 6).

It is striking that none of the 12 compounds without any

hepatic metabolism had any identifiable reports of liver failure, liver transplantation, or fatal DILI. This does not necessarily mean that compounds without hepatic metabolism are entirely immune from hepatotoxicity, but it is significantly less likely. One example of a drug in which selective hepatic metabolism did not cause serious hepatotoxicity is ximelagatran, which was not approved by the Food and Drug Administration due to cases of hepatotoxicity during Lumacaftor its development.9–10 Because this medication was never approved for clinical use in the United States, it was not included in our study. Another example is pregabalin, which is also without hepatic metabolism but may be rarely associated with suspected severe hepatotoxicity.20 Because it was approved in December 2004, it was not included in our brand name compound category. Thus, lack of hepatic metabolism does not assure total lack of hepatotoxicity, but based on our data it indeed appears to be quite rare. According to the pharmacological interaction hypothesis, some drugs may be able to initiate an immune response through a reversible interaction with the major histocompatibility complex–T cell receptor complex.21 It has been postulated that ximelagatran leads

to hepatotoxicity by evoking an immune response by binding directly but reversibly to major histocompatibility selleck chemical complex.10 Second, we did not find a significant relationship between the frequency of hepatic adverse events and whether a compound is

metabolized by phase I and/or phase II reactions. Compounds with only phase II metabolism were not immune from hepatic adverse events. If confirmed, these observations are important, because they argue against a singular role for reactive metabolites 上海皓元医药股份有限公司 generated by phase I reactions in causing hepatotoxicity. Third, we found a statistically significant relationship between reports of jaundice and whether a compound has biliary excretion. Although it was not always clear from the reports contained within the DRUGDEX whether jaundice is hepatocellular or cholestatic in nature, we found that it was cholestatic in a substantial proportion. This leads us to speculate that compounds with biliary excretion may cause cholestatic jaundice in genetically predisposed individuals (e.g., defective transporters). There is increasing evidence that cholestatic liver injury associated with certain compounds results from a drug- or metabolite-mediated inhibition of hepatobiliary transport systems.22 Furthermore, we observed an additive effect of daily dose and hepatic metabolism; oral compounds with significant hepatic metabolism but also given at daily doses ≥50 mg had the highest risk of hepatic adverse drug reactions compared with other groups (Table 6).

It is striking that none of the 12 compounds without any

hepatic metabolism had any identifiable reports of liver failure, liver transplantation, or fatal DILI. This does not necessarily mean that compounds without hepatic metabolism are entirely immune from hepatotoxicity, but it is significantly less likely. One example of a drug in which selective hepatic metabolism did not cause serious hepatotoxicity is ximelagatran, which was not approved by the Food and Drug Administration due to cases of hepatotoxicity during MLN8237 mw its development.9–10 Because this medication was never approved for clinical use in the United States, it was not included in our study. Another example is pregabalin, which is also without hepatic metabolism but may be rarely associated with suspected severe hepatotoxicity.20 Because it was approved in December 2004, it was not included in our brand name compound category. Thus, lack of hepatic metabolism does not assure total lack of hepatotoxicity, but based on our data it indeed appears to be quite rare. According to the pharmacological interaction hypothesis, some drugs may be able to initiate an immune response through a reversible interaction with the major histocompatibility complex–T cell receptor complex.21 It has been postulated that ximelagatran leads

to hepatotoxicity by evoking an immune response by binding directly but reversibly to major histocompatibility this website complex.10 Second, we did not find a significant relationship between the frequency of hepatic adverse events and whether a compound is

metabolized by phase I and/or phase II reactions. Compounds with only phase II metabolism were not immune from hepatic adverse events. If confirmed, these observations are important, because they argue against a singular role for reactive metabolites 上海皓元医药股份有限公司 generated by phase I reactions in causing hepatotoxicity. Third, we found a statistically significant relationship between reports of jaundice and whether a compound has biliary excretion. Although it was not always clear from the reports contained within the DRUGDEX whether jaundice is hepatocellular or cholestatic in nature, we found that it was cholestatic in a substantial proportion. This leads us to speculate that compounds with biliary excretion may cause cholestatic jaundice in genetically predisposed individuals (e.g., defective transporters). There is increasing evidence that cholestatic liver injury associated with certain compounds results from a drug- or metabolite-mediated inhibition of hepatobiliary transport systems.22 Furthermore, we observed an additive effect of daily dose and hepatic metabolism; oral compounds with significant hepatic metabolism but also given at daily doses ≥50 mg had the highest risk of hepatic adverse drug reactions compared with other groups (Table 6).

CTLA-4 is not constitutively expressed on effector T cells but is rapidly induced upon TCR engagement.14 In patients with CHB, we found a greater propensity for the induction of CTLA-4 upon TCR stimulation with either mitogen or cognate peptide, with CTLA-4 induction in HBV-specific CD8 T cells correlating strongly with viral load. These data are in line with recent demonstrations that CTLA-4 plays a critical role in the effector T-cell compartment in addition to its contribution to regulatory T-cell function.15, 16 CTLA-4 mediated inhibition may depend

on the fact that it shares ligands (B7-1 and B7-2) with CD28 but has higher avidity; when the supply BVD-523 nmr of these ligands is limited, CTLA-4-mediated inhibitory signaling could override CD28-mediated positive costimulation.

In CHB, the ability of CTLA-4 to outcompete CD28 may be favored not only by the increase in CTLA-4, but also by the reduced levels of CD28 on CD8 T cells17 and by the scarcity of B7 Selleck Palbociclib ligands on hepatocytes and other intrahepatic cells with antigen-presenting capability.18 We postulated that CTLA-4-mediated coinhibition may be one of the pathways that drives T cells encountering their antigen in the liver towards Bim-dependent apoptosis. In support of this, we found the highest intracellular levels of Bim in CTLA-4hi HBV-specific CD8 T cells. We speculate that CTLA-4 signaling may induce Bim by its capacity to reduce availability of IL-214 while increasing

cell-intrinsic transforming growth factor beta (TGF-β),19 which is up-regulated at the transcriptional level in HBV-specific CD8 T cells2 and can promote Bim-dependent attrition of LCMV-specific T cells.20 In most patients with CHB without evidence of liver inflammation, blocking the CTLA-4 receptor was able to reduce Bim expression. However, in patients with CHB-related liver inflammation the lack of reduction in Bim achieved by CTLA-4 blockade invoked a dominant role for other factors in driving this proapoptotic phenotype. We have recently described a signaling defect reducing cell-autonomous production of IL-2 in patients with CHB-related liver inflammation17 medchemexpress that may limit the efficacy of CTLA-4 blockade in such patients. In addition, as discussed below, a number of different coinhibitory pathways may play nonredundant roles in T-cell exhaustion in CHB. To explore the therapeutic potential to reprogram the tolerogenic phenotype of HBV-specific CD8 T cells we examined the impact of antiviral therapy. A previous study of CD8 T-cell reconstitution on antiviral monotherapy had suggested that viral load reduction resulted in some increase in cytolytic responses against HLA-A2 restricted HBV epitopes,21 but that these were of limited lifespan.

[37] With caudal shifting, a safe and tension-free DDA can be fashioned, although the long-term efficacy of this technique still needs further verification. It is important to note that skeletonization of the common hepatic duct will jeopardize its blood supply and thus must

be prohibited. There is no definite evidence that method of BR is related to BAS.[13, 38] A retrospective study by our center compared DDA and HJ in terms of the incidence of BAS after adult RLDLT but observed no difference. However, another retrospective study comparing the two methods found that DDA was this website associated with a significantly higher chance of BAS after pediatric LDLT using grafts from left livers.[39] A recent study reported that the routine use of microsurgical BR in pediatric LDLT greatly reduced the rate of BAS.[24] All in all, a randomized controlled trial comparing DDA and HJ PLX4032 in vitro is needed before any one of them can claim superiority. Impaired blood supply damages the bile duct. Blood supply of the bile duct is mainly from the arterial system,[40, 41] and skeletonization of the duct renders it ischemic. The supraduodenal periductal plexus supplies the graft

bile duct. Dissection around the hilar plate should be kept to the minimum. Ikegami et al.[25] reported that the technique of minimal hilar dissection resulted in a significantly lower incidence of BAS after adult LDLT with DDA when compared with the conventional technique (14.6% vs 32.1%, P = 0.003). Complete hilar plate encircling can also preserve the periductal blood

supply since the bile duct and the hepatic artery are located within the same hilar sheath.[20] Biliary anomaly in grafts poses a technical challenge and is associated with a higher incidence of transplant failure. About two thirds of right-lobe grafts contain a single right hepatic duct, and the vast majority of the remaining one third contain two hepatic ducts.[42] As a corollary, most of the time, BR is done by anastomosing a single graft duct with an opening in the recipient duct or jejunum. If necessary, reduction ductoplasty is performed.[24] If there are two graft ducts and they are not more than 5 mm apart, DDA can be performed 上海皓元医药股份有限公司 with incorporation of the hilar plate. Lin et al.[24] have described four methods for BR with two graft ducts: (i) The two graft ducts are merged into one opening by ductoplasty and the opening is then anastomosed with an opening in the recipient duct or jejunum. This method is used when the distance between the two graft ducts is not bigger than the diameter of the smaller duct opening. (ii) The two graft ducts are anastomosed with two openings in the recipient duct or jejunum. This “2-to-2 unmixed reconstruction” is used when the distance between the two graft ducts is bigger than the diameter of the smaller duct opening. (iii) One of the two graft ducts is anastomosed with the recipient duct and another with the recipient jejunum.

4a),[77] demonstrating the infectivity of HEV in Palbociclib pig liver that was for sale for human consumption. Taken together, although there is currently no direct evidence to prove HEV infection from pigs to humans, it is beyond doubt that pigs are the most important animal reservoir for HEV infection in humans in Japan, especially in Hokkaido, where the highest number of patients with

hepatitis E have been reported, most likely due to the consumption of pig meat/viscera (Table 4). Wild boars (Sus scrofa) are indigenous to many countries worldwide, including Japan, posing ecological and infectious disease concerns. In some countries including Japan, recreational hunting of wild boars and the consumption of boar meat provides an increased risk for the transmission of various pathogens, such as HEV, from wild boars to humans. The prevalence of HEV infection among wild boars in Japan has been investigated by many researchers, and the findings are summarized

in Table 5.[32, 79-84] The HEV seropositivity in wild boars varied from 4.5% to 34.3%, and the HEV RNA detection rate ranged 1.1–13.3% in wild boars from different geographical regions in Japan. In 2003, Matsuda et al.[18] reported, for the first time, two patients who developed a severe HEV infection after consuming raw liver from a wild boar. Later, Shimizu et al.[85] described four cases of acute hepatitis E in Aichi prefecture that occurred after the ingestion of boar meat. The HEV strains isolated from these patients that belonged to genotype 4, formed a single cluster, and were 98.8–99.7% identical to those recovered from wild boars captured in the same prefecture. Fer-1 manufacturer Zoonotic food-borne transmission of HEV from wild boars to humans has been demonstrated by analyzing a case of hepatitis E caused by ingestion of boar meat, with the HEV strain sharing 99.95% nucleotide sequence identity with that in the leftover boar meat the patient had eaten.[19] Upon inoculation of A549 or PLC/PRF/5 cells with HEV in liver homogenates at 9.8 × 105 copies MCE per well or more (six-well plate), the boar HEV multiplied efficiently (Fig. 4b) and produced infectious

progeny viruses.[77] These findings indicate that wild boars are another important reservoir for HEV in humans. Most strains of HEV recovered from wild boars worldwide belong to genotype 3.[30] However, in Japan, boar HEV strains of not only genotype 3, but also genotype 4, have been detected. In addition, two novel HEV strains (JBOAR135-Shiz09 and wbJOY_06) belonging to unrecognized genotypes (provisionally designated as genotypes 5 and 6, respectively) have been recovered from wild boars in Japan.[86-88] It remains unknown whether these novel HEV strains can be transmitted to humans, and are also part of the reservoir for HEV. In 2003, Tei et al.[17] reported four patients who became infected with HEV after eating venison.