O’Leary – Consulting: Gilead, Jansen Laura M. Kulik – Advisory Committees or Review Panels: Bayer/ Onyx; Grant/ Research Support: Bayer/Onyx; Speaking and Teaching: Bayer/Onyx, Nordion, Gilead Shailesh Chavan – Employment: Biotest Pharmaceuticals Christopher J. Dougherty – Employment:

Biotest Pharmaceuitcals Corporation The following people have nothing to disclose: George Therapondos, selleck inhibitor Roshan Shrestha, Jeffrey Campsen, James Spivey, Jens Rosenau, Kalyan R. Bhamidi-marri, Lewis W. Teperman, Gerond Lake-Bakaar, Fredric D. Gordon, Daniel Maluf Fibrosing cholestatic hepatitis (FCH) is a rare but severe form of HCV-recurrence following liver transplantation (LT) leading to poor short term survival. Therapeutic options are limited. Study aims were to assess efficacy and tolerance of sofosbuvir

(SOF) and daclatasvir (DCV)-based regimens in this setting. Methods: The CUPILT study is a prospective nationwide cohort including patients with HCV-recurrence following LT treated by new antivirals. The present work focused on 21 patients diagnosed with FCH and included between Oct 2013 and Feb 2014. FCH diagnosis was based on strict criteria including histological review by an expert pathologist. Treatment regimens were prescribed at investigator’s discretion. Patients were followed at W0, W1, W2, W3, W4, W6, W8 and W12. Results: FCH was diagnosed after a median duration of 6 months [range 1-18] following LT and therapy started at 10 months [2-38] post LT. Features of patients at W0 were: median IWR-1 cell line filipin age: 53 years [36-67], men: 81%, G1: 76%, G3: 10%, G4: 14%, ALT: 128 IU/L [46-588], gGT: 595 IU [86-5,511], bilirubin: 6.0 mg/dL [0.6-19], albumin : 3.2 g/dL [1.6-4.0], HCV RNA : 6.9 log IU/ml [4.6-8.4]. Ascites was observed in 8 (38%) patients. Four (19%) were HIV-co-infected and 14 (67%) failed

to antiviral therapy containing protease inhibitors in 9 (43%) cases. The following regimens were used: Peg-IFNa + SOF + RBV (n=2), SOF + RBV (n=6), SOF + DCV (n=1) and SOF + DCV + RBV (n=12) for 24 weeks. All patients were alive without re-transplantation at W12. HCV RNA was not detectable at W2 and W4 in 1 (5%) and 3 (14%) patients, respectively. At W12, 20 (95%) patients had HCV RNA <15 IU/ml and 17 (81%) were not detectable. Early viral kinetics was not influenced by treatment regimens. The rates of ALT and gGT normalization at W12 were 76% and 52%, respectively. Median bilirubin serum levels rapidly decreased from 6.0 to 3.6 at W1 and 2.6 mg/dL at W2. The median time to achieve bilirubin levels below 2 mg/dL was 6 weeks. At week 12, 19 (90%) of patients had bilirubin below 2 mg/dl, and 13 (69%) below 1 mg/dL. Albumin levels increased from 31 to 36 g/L at W12. This was accompanied by clinical improvement including nutritional status (weight gain from 67.5 to 70.0 Kg). Ascites disappeared in 4/8 patients, but remained stable in 2 patients who had initially refractory ascites.

We analyzed brain activity during infusion of acid or isotonic saline into the esophagus using group independent component selleck screening library analysis (ICA),4 a general method that does not depend on a priori information of the task. Six healthy male

volunteers (29–45 years old) were studied. All the volunteers gave us written informed consent for participation of the study, and the study protocol was approved by the Internal Review Board of Juntendo University Hospital. A multi-lumen catheter was inserted transnasally and side-hole infusions ports were approximately 15 cm proximal to the lower esophageal sphincter. The experimental protocol was a 5-min interval, 5-min isotonic saline infusion, 5-min interval, 5-min 0.1 N HCl infusion and a final 5-min interval. The infusion rate for both saline and HCl was 2 mL/min. Subjects were left uninformed of the experimental protocol, and did not know when and what kind of liquid was infused into the esophagus. When the subjects perceive heartburn,

they immediately push a button-response device, and then push the button twice soon after the cessation of a heartburn episode. They were also questioned selleck kinase inhibitor about the feeling during magnetic resonance (MR) scanning after the end of the examination. Magnetic resonance images were acquired on a Philips 3.0 Tesla MR scanner (Philips Medical Systems, Andover, MA, USA), using the following parameters: repetition time, 6 s; echo time, 35 ms; slice thick, 6 mm; field of view, 240 × 240 mm2; matrix size, 64 × 64. A total of 250 functional images Non-specific serine/threonine protein kinase consisting of an echo planar scan were obtained for each

of the 22 slices over a 25-min period. Subjects kept their eyes closed during MR scanning. Realignment, normalization, and smoothing as preprocessing were performed for the MRI data using SPM 2 (Wellcome Trust Centre for Neuroimaging, London, UK).5 Head movement was corrected by realignment, the realigned images were moved into the same Montreal Neurological Institute space by normalization, and normalized images were smoothed with an 8-mm Gaussian spatial filter. Smoothed data were analyzed using GIFT v1.3d,6 a group ICA approach. First, setup was done, and a number of independent components from the data were extracted. Second, analysis was run and the result was visualized using the component explorer. Group ICA was applied to fMRI data during the first interval, saline infusion, and HCl infusion. The results were inspected manually to detect interesting components. Masks for region of interest analysis version 0.6.1. (Bender Institute of Neuroimaging, University of Giessen, Giessen, Germany)7 were used to identify the cerebral region of the interesting components. Subjects did not have any heartburn, and never pushed the response device. But, all the subjects were aware of the presence of the feeding tube in the esophagus during MR scanning. Two subjects felt the infusion of liquid.

The effect of IFN therapy was evaluated by measurement of the serum HCV RNA level at 6 months after completion of the therapy. Although all treatments were covered by the National Health Insurance of Japan, they were performed with the approval of the institutional review board of Jikei University School of Medicine. Figure 1 shows the fluctuations of serum HCV RNA levels of each patient. In both patients, sustained viral response was achieved by combined DFPP plus 24 weeks of i.v. IFN-β therapy. While twice-daily injections of IFN-β for 2 weeks could be completed, there were no adverse

Selleck PD0325901 events, including DFPP, that necessitated discontinuation or reduction in the dose of IFN-β. PERSISTENT HCV INFECTION has been suggested by a number of studies as an important prognostic factor in HD patients. Because serum levels of aspartate aminotransferase selleck compound and alanine aminotransferase are low in HD patients, it is difficult to determine the presence or absence of hepatic disease in these patients.[9] Consequently, the

natural history of HCV infection in HD patients has not yet been clearly elucidated. However, the frequency of deaths associated with hepatic disease in HD patients is too high to ignore in terms of the cause of death.[10] Moreover, liver biopsy performed in HD patients, although in a small number of patients, has revealed similar histological progression of hepatic disease to that in

non-HD patients.[11] These data suggested the importance of HCV eradication by antiviral therapy to improve the prognosis of HD patients with HCV infection and both US and Japanese guidelines recommended antiviral therapy in HD patients.[12, 13] In addition, the therapeutic effect of IFN monotherapy is reported to be superior in HD patients as compared with that in non-HD patients.[14] However, one of the big obstacles to effective treatment of HCV infection in HD patients is that ribavirin, which enhances the therapeutic effects of IFN, has a critical disadvantage on account of the inevitable occurrence many of hemolysis as an adverse effect in HD patients.[15] It has been reported that a reduced dose of ribavirin can be applied with IFN in HD patients, however, tuning of ribavirin dose is very difficult, and monitoring of serum concentration of ribavirin may be essential in continuing the therapy.[16] The effects of IFN monotherapy administrated according to the current protocol are extremely limited in patients with HCV genotype 1b infection with elevated blood HCV RNA levels. Herein, we have shown that a combination of virus eradication from the blood by DFPP plus twice-daily injections of IFN-β, which enhances the antiviral effects of IFN, reduced the blood HCV RNA levels to below the detectable level in the early stage of treatment, similar to that previously reported in the case of non-HD patients.

The vast majority of patients carry the missense Cys282Tyr mutation of the HFE gene. Hepcidin, the central regulator of iron homeostasis, is deficient

in HH, leading to unchecked iron absorption and subsequent iron overload. The bone morphogenic protein (BMP)/small mothers against decapentaplegic (Smad) signaling cascade is central to the regulation of hepcidin. Recent data from HH mice models indicate that this pathway may be defective in the absence of the HFE protein. Hepatic selleck chemicals BMP/Smad signaling has not been characterized in a human HFE-HH cohort to date. Hepatic expression of BMP/Smad-related genes was examined in 20 HFE-HH males with significant iron overload, and compared to seven male HFE wild-type controls using quantitative real-time reverse transcription polymerase chain reaction. Hepatic expression of BMP6 was appropriately elevated in HFE-HH compared to controls (P = 0.02), likely related to iron overload. Despite this, no increased expression of the BMP target genes hepcidin

and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling occurs in HFE-HH. Furthermore, Smad6 and Smad7, inhibitors of BMP signaling, were up-regulated in HFE-HH compared to controls (P = 0.001 and P = 0.018, respectively). Conclusion: New data arising Selleckchem PF-01367338 from this study suggest that impaired BMP signaling underlies the hepcidin deficiency of HFE-HH. Moreover, the inhibitory Smads, Smad6, and Smad7 are identified as potential disruptors of this signal and, hence, contributors to the pathogenesis of this disease. (HEPATOLOGY 2010;) Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by iron overload. Unregulated iron absorption from the intestine and release from macrophages primarily affects the liver, the main storage site of this essential mineral. Left untreated, iron excess may

progress to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.1, 2 The most common form of HH (type 1) results from the missense Cys282Tyr (C282Y) mutation of the HFE (hemochromatosis) gene. Although it is a disease of variable penetrance and considerable heterogeneity, the vast majority of patients with HH are homozygous for Resminostat the C282Y mutation.3, 4 The mutant C282Y HFE protein is unable to bind beta-2-microglobulin and fails to reach the cell membrane, resulting in a misfolded, nonfunctional protein.5 HFE represents a nonclassical major histocompatability complex type 1 molecule expressed in several different tissues. Liver-specific HFE knockout in animal models resulted in a phenotype similar to HFE-HH, suggesting the liver is where HFE exerts its main effect on iron metabolism.6, 7 Upon interacting with diferric transferrin and transferrin receptor 1 (TfR1) at the hepatocyte cell surface, HFE is thought to shift to form part of an iron-sensing complex through its interaction with TfR2.

Anti-CD19, anit-CD4, and anti-CD8 microbeads were used as recommended by the manufacturer (Miltenyi Biotech Inc., Auburn, CA).26 Briefly, CD19+ cells were first positively selected with an MS MiniMACS column (Miltenyi Biotech) from total PBMCs; the flow-through CD19− cell population was subjected to CD4+

T-cell positive separation. Furthermore, the flow-through CD19− CD4− cells were used DAPT to isolate CD8+ T cells. Each cell pellet was resuspended in 500 μL RNAlater (Applied Biosystems, Foster City, CA). To stimulate B cells, 2.0 × 105 CD19+ B cells and 8.0 × 105 CD19− non-B cells with 2 μM CpG-B (InvivoGen, San Diego, CA) were cultured in 48-well flat-bottomed plates in 500 μL RPMI 1640 (Invitrogen, Carlsbad, CA) supplemented with 10% heat-inactivated fetal bovine serum (FBS; GIBCO-Invitrogen Corp., Grand Island, NY), 100 μg/mL streptomycin, and 100 U/mL penicillin (Invitrogen) for 96 hours at 37°C in a 5% CO2 humidified atmosphere. After 96 hours of culture, supernatants were collected and clarified by centrifugation. PBMCs from patients with PBC were resuspended in staining buffer (0.2% BSA, 0.04% EDTA, 0.05% sodium azide in PBS), AZD1208 divided into 25-μL aliquots, and incubated with anti-human FcR blocking reagent (eBioscience,

San Diego, CA) for 15 minutes at 4°C. The cells were then washed and stained with the following antibodies for 30 minutes at 4°C: Fluorescein isothiocyanate-conjugated (FITC)-anti-CD4 (BD Pharmingen, San Diego, CA) CD8 (BD Pharmingen) FITC-anti-CD20 (eBioscience) Phycoerythrin-conjugated (PE)-anti-CD45RO (BD Pharmingen) PE-anti-CD38 (eBioscience) PE-Cy-Chrome (PE-Cy5)-anti-CD56 (BD Pharmingen) TRI-COLOR (TC)-anti-CD25 (Invitrogen/Caltag, Carlsbad, CA) Allophycocyanin-conjugated (APC)-antiCD19 (eBioscience) Alexa Fluor 750 (AF750)-conjugated-anti-CD27 (eBioscience). IgG isotype controls were used for negative controls. The cells were then washed once with PBS containing 0.2%

BSA. After staining, the cells were washed and fixed with 1% paraformaldehyde in PBS. For analysis, stained cells were counted on a FACScan flow cytometer (BD Immunocytometry Systems) that had been upgraded by Cytek Development (Fremont, CA) Carnitine dehydrogenase to allow for five-color analysis. The acquired data were analyzed with Cellquest PRO software (BD Immunocytometry Systems). Total RNA was extracted using the MagMAX-96 Total RNA Isolation Kit (Applied Biosystems). One million cells of total RNA was reverse-transcribed with SuperScript III Reverse Transcriptase (Invitrogen) and oligo dT20 primer (Invitrogen), and quantified on an ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Amplification was performed for 40 cycles in a total volume of 12 μL, and products were detected using RT2 SYBR Green (SABiosciences, Frederick, MD).

Current U.S. politics is moving toward an attitude of universal health coverage as the new moral high ground, generating an overriding expectation and attitude toward accessing comprehensive, quality health care for every individual. While dentistry has responded with various outreach programs, dissatisfaction prevails from the underserved, and their voice has become more resounding and has been complimented by the current political and economic check details environment. This outcry has been reinforced and the issue compounded by cuts in federal and state dental programs. For example, there is substantial

reduction in adult dental care (Denti-Cal) available in California (http://www.denti-cal.ca.gov, http://www.medi-cal.ca.gov, Trametinib manufacturer http://www.dhcs.ca.gov). Another factor influencing the future of dentistry can be readily observed with the ever-expanding line of dental procedures being allocated to

dental auxiliaries. Even though dental practitioners are very caring, there has been a slow erosion of diagnostic accountability among dentists, and an expanding emphasis on procedural-based care. This has accompanied the constant evolution of expanding dental procedures to ancillary providers, taking away from the direct professional expertise anticipated by patients. As many of these procedures generate a lowered practice profile, the stage is set for the transfer of more of these responsibilities to non-dentists. All these activities appear to be converging factors and have created opportunities to change the entire landscape of dental care. Following the non-dentist provisions allowed in Alaska, the Minnesota legislature recently approved new “mid-level” providers. Pressure from the governor and support from other sources, such as the dental hygiene association and the medical counterpart of mid-level care community (physicians’ Dolutegravir concentration assistants and nurse practitioners), there has been a substantial supporting voice in the political arena.

This culminated with the proposed establishment of a state licensed profession, the “dental therapist” and the “advanced dental therapist.” An initial and necessary response came from the Dean of the University of Minnesota School of Dentistry, ACP Past President Dr. Patrick Lloyd, who looked into international models as they currently exist (Reference: ADA News; June 1, 2009; “University of Minnesota reviewing applications for nation’s first dental school-based dental therapy program”). Dr. Lloyd appropriately recommended that a program be developed within the dental school, whereby diagnosis and treatment planning, using the oversight of dentists, would allow for a 2-year graduate as a dental therapist.

Immunofluorescence analysis illustrated that nucleus FOXO3a was dramatically decreased in WB-TβLT cells compared with WB-CON cells (Fig. 5C), and it could be restored by overexpression of the dominant-negative mutant of Akt (Fig. 5D), which implies that Akt-mediated exportation and

subsequent degradation of FOXO3a might be, at least partially, involved in LPCs transformation upon TGF-β treatment. More important, overexpression of DN-Akt diminished the proportion of T-ICs (Fig. 5E, Table 1) in WB-TβLT cells and attenuated their self-renewal capacity (Fig. 5F). To clarify how TGF-β regulates the activation of Akt, we determined the PI3K activity in WB-TβLT cells. As shown in Fig. https://www.selleckchem.com/products/hydroxychloroquine-sulfate.html 6A, there Panobinostat was no significant difference of PI3K activity between WB-TβLT and the control cells. Interestingly,

WB-TβLT cells with elevated levels of phosphorylated Akt displayed dramatically reduced PTEN expression (Fig. 6B), suggesting PTEN was involved in the activation of Akt. Among the three miRNAs previously reported to suppress PTEN expression,30, 31 the level of miR-216a was obviously up-regulated in WB-TβLT cells compared with WB-CON, whereas miR-217 was only slightly increased and miR-21 remained invariable (Fig. 6C). Mouse-derived liver progenitor cell line (LEPCs) was subjected to long-term treatment with TGF-β and consistent results were achieved (Supporting Fig. 7). Specific antagomir against miR-216a notably rescued PTEN expression and attenuated Akt phosphorylation, whereas down-regulation of miR-217 had a marginal effect (Fig. 6D). Moreover, antagomir-216a evidently reduced the proportion of stem cells in WB-TβLT cells (Fig. 6E, Table 2) and suppressed their self-renewal capacity (Fig. 6F). Suppression of Smad3 by its specific

inhibitor or repression of Smad2 by small interference RNA not only attenuated the up-regulation of miR-216a and down-regulation of PTEN, but also impaired the T-IC characteristics Dichloromethane dehalogenase of WB-TβLT cells (Supporting Fig. 8). Therefore, constant activation of Akt elicited by miR-216a-mediated PTEN suppression is involved in the T-ICs generation from LPCs exposed to TGF-β. TGF-β has been well accepted to be critical in the process of liver fibrosis and cirrhosis. However, the role of TGF-β in HCC occurrence remains elusive.4, 32 With this report we first proposed the association of TGF-β with hepatic T-ICs generation during hepatocarcinogenesis. Our data revealed that TGF-β exposure could induce the transformation of LPCs and give rise to hepatic T-ICs. We also demonstrated that hyperactivation of Akt was required in TGF-β-induced malignant transformation of LPCs. Suppression of PTEN by miR-216a was responsible for Akt hyperactivation in LPCs upon TGF-β exposure.

As

prior HCV screening efforts have not targeted Emergency Department (ED) baby boomer patients, we describe early experience with Opaganib molecular weight integrated opt-out HCV antibody screening of medically stable “baby boomers” presenting to an urban academic ED. We performed HCV antibody testing 24 hours per day and confirmed positive test results using PCR. The primary outcome was prevalence of unrecognized HCV infection. Among 2,325 unique HCV-unaware baby boomers, 289 (12.7%) opted-out of HCV screening. We performed HCV-antibody tests on 1,529 individuals, of which 170 (11.1%) were reactive. Among antibody reactive cases, follow-up PCR was performed on 150 (88.2%), of which 102 (68.0%) were confirmed RNA-positive. HCV antibody reactivity was more likely in males compared to females (14.7% vs. 7.4%, p<0.001), African Americans compared to whites (13.3% vs. 8.8%, p=0.010), and underinsured/ uninsured patients compared to insured patients (16.8%/ 16.9% vs. DAPT research buy 5.0%, p=0.001). Linkage-to-care service activities were recorded for 100 of the 102 confirmed cases. Overall, 54 (54%) RNA-positive individuals were successfully contacted by phone within five call back attempts. We confirmed initial follow-up appointments for 38 (70.4%) RNA-positive individuals successfully contacted, and 21

(55.3%) individuals with confirmed appointments attended their initial visit with a liver specialist; three (7.9%) are awaiting an upcoming scheduled appointment. Conclusion: We observed high prevalence of unrecognized chronic HCV infection in this series of baby boomers presenting to the ED highlighting the ED as an important venue for high-impact HCV screening and linkage to care. (Hepatology 2014;) “
“A 44-year-old woman with hepatitis C cirrhosis presented with a week of heavy vaginal bleeding. Her obstetric history was significant for three cesarean sections. Her gynecologist made an initial diagnosis of menometrorrhagia exacerbated by thrombocytopenia and coagulopathy.

Computed tomography eltoprazine (CT) angiography revealed splenic vein thrombosis and engorged pelvic veins which arose as collaterals from the splenic vein (Fig. 1). Hysteroscopy could not identify a culprit lesion due to the rapidity of bleeding. A transjugular intrahepatic portosystemic shunt (TIPS) was created and thrombectomy of the splenic vein was performed and the residual partially occlusive thrombus was then stented. Hepatopedal flow was then noted from splenic vein to portal vein and through the TIPS. Hysteroscopy showed persistently engorged varices. Venous embolization of the varices was performed with a combination of embolization coils and a vascular plug (Fig. 2). Recovery was uneventful, and she was followed for 2 years in our clinic without further vaginal bleeding. CT, computed tomography; TIPS, transjugular intrahepatic portosystemic shunt.

A significantly higher expression of pSmad2/3L-Thr in specific epithelial cells in the gastric mucosa of H. felis-infected mice with gastritis could be found. The authors suggested that these cells might be epithelial stem cells [41]. Undoubtedly, one of the most exciting articles published this year in the field came from Chow and Mazmanian [42]. Using an elegant intestinal epithelial cell coculture model coupled with adoptive cell transfer studies, it was shown that the H. hepaticus type VI secretion system (T6SS) appears to promote a symbiotic relationship between the microbe and host. Presence of the

T6SS was demonstrated to limit intestinal epithelial cell invasion and also to elicit anti-inflammatory activity aimed at promoting a balanced relationship with the host. H. hepaticus

has also been shown to modulate constitutive macrophage responses to make them more anti-inflammatory, MG-132 price increasingly phagocytic, and resistant to secondary stimulation [43]. A second study also showed that H. hepaticus could alter TLR4 adaptor protein usage and demonstrated distinct roles for MyD88 and Trif signaling pathways in the context of intestinal ischemia–reperfusion (IR) in the presence of H. hepaticus infection [44]. A similar finding was also demonstrated in a model of hemorrhage-induced tissue damage with H. hepaticus infection shown to modulate the mechanism of intestinal damage and inflammation [45]. In early 2010, Fox et al. STK38 [46] also reported that H. hepaticus infection could promote Imatinib price liver tumors in hepatitis C transgenic mice. The study showed that H. hepaticus colonization of the intestine could promote HCV- and aflatoxin-induced tumors with NF-kB signaling identified as pivotal to the process. This work was followed by the identification that Helicobacter marmotae-associated inflammation could also act as a tumor promoter [47]. Interestingly, in contrast to the previous H. hepaticus studies, H. marmotae-associated hepatic lesions

did not progress as extensively with no evidence of hyperplasia or necrosis detected. Differences in the pathogenic capabilities of Helicobacter species have been documented previously in some cases resulting in opposing effects in a specific disease model [48]. Further evidence to support these differential responses was provided through a study by Eaton et al. [49]. A Helicobacter-infected Smad3 knockout mouse model used for therapeutic colorectal cancer studies was investigated for its usefulness in identifying early stage disease including potentially prior to disease onset [50]. Noncontrast-enhanced MRI could detect MUC lesions in 58% of histologically confirmed cases at 8 weeks postinfection; however, serial imaging produced inconsistent results.

, 2010), but that it is among the poorest performers. Under almost all loadings, mean and maximal VM strain values between the two polar bear specimens are closer to each other than to any other species. This is supported by the results of pairwise two-factor ANOVA. Table 2 shows that at α = 0.1, P < α for all possible pairs of polar bears and other species, except between polar bear (SAM-ZM 35814) and polar bear (AM M42656), suggesting that the mean VM brick strain distributions in the two polar bears are statistically similar. Our finding that the polar bear is arguably the poorest

performer is surprising given its status as the only living hypercarnivorous ursid. check details Our results agree with a recent analysis. (Slater et al., 2010), which compared the mechanics of a polar bear cranium with those of a brown bear, from which polar bears have recently diverged (Lindqvist et al., 2010). We suggest that the skull biomechanics of the polar bear, which primarily ingests easily processed

blubber (Perry, 1966), are consistent with predation upon relatively small prey. Moreover, its primary prey is semiaquatic and poorly equipped to resist capture on land. Regarding diet in A. africanum, it was clearly capable of generating very high bite forces for its size, and its skull was well-adapted to resist both these and relatively Ivacaftor supplier high extrinsic loads, and these are features that would be expected in a species that regularly kills and/or scavenges on relatively large prey. However, our results also show that the exclusively herbivorous giant panda is similarly well-adapted to sustain relatively Molecular motor high loadings, indicating that ursid feeding behaviour cannot be predicted on the basis of our FEA alone. Many craniodental variables have

been considered by previous authors. Relative grinding area (RGA) is perhaps the most reliable indicator of the relative importance of plant material in the diet, with low values correlating with decreased reliance on plants (Sacco & Van Valkenburgh, 2004). On this basis, it is unlikely that similarities in mechanical performance between the A. africanum and the giant panda are a consequence of similarities in diet. We calculate a value of 1.47 for RGA in our specimen of A. africanum, well below values for RGA evidenced in any living bears, the next lowest being 1.83 in the polar bear (Van Valkenburgh, 1989). Relative carnassial blade length (RBL) has also been regarded as a strong indicator of the importance of vertebrate prey in carnivoran diets, and RBL in A. africanum is also considerably higher than in extant bears. However, among extant bears, the only hypercarnivore that has relatively short carnassial blades is the polar bear (Sacco & Van Valkenburgh, 2004), perhaps because it feeds mostly on blubber as opposed to meat or bone (Perry, 1966), as previously mentioned.