Lions are a clear threat to giraffes.

Observational studies indicate that giraffes alter their behavior in the presence of lions. A typical vigilance posture is shown in Supporting Information Fig. S1. When lions are nearby, giraffes avoid waterholes (Valeix et al., 2009a), where they are particularly vulnerable (Dagg & Foster, 1982; Périquet et al., 2010), and favor open grasslands over denser vegetation (Valeix et al., 2009b). Females with young calves spend a disproportionate amount of time in open habitats, sacrificing browse availability for improved ability to detect and evade predators (Young Autophagy Compound Library purchase & Isbell, 1991). Calves often remain in open areas in crèche groups, while mothers travel to feed (Langman, 1977; Leuthold, 1979; Mejia, in Moss, 1982). Carcass records from southern Africa reveal that lions kill more male than female giraffes (Hirst, 1969; Pienaar, 1969; Owen-Smith, 2008) and that predation on giraffes is highest in the mid- to late dry season (Hirst, 1969; Owen-Smith, 2008). However, it can take years to acquire a reasonably sized carcass sample and these records suffer from the underrepresentation of rapidly consumed calves (Hirst, 1969; Dagg & Foster, 1982; Owen-Smith & Mills, 2008). The mechanics and frequency of lion attacks and the circumstances in which giraffes are

able to evade attacks remain unclear. Easily collected claw-mark data reduce these gaps in knowledge. We used lion claw marks on Masai giraffes Giraffa camelopardalis tippelskirchi living in Serengeti National Park,

Tanzania to elucidate lion attack behavior SRT1720 research buy and predation patterns. Specifically, we studied relationships between claw marks and giraffe medchemexpress age, sex, herd size, height and study area, and we used supplemental carcass data from the Serengeti Lion Project to examine seasonal effects. We integrate our findings with results from prior studies on lion–giraffe interactions. Serengeti National Park forms part of the 25 000-km2 Serengeti ecosystem, a region of northern Tanzania and southern Kenya that supports large numbers of resident and migratory ungulates and, consequently, high numbers of predators, including lions (Sinclair & Norton-Griffiths, 1979). Giraffes were sampled in 3 non-neighboring areas of Serengeti during each dry season between August 2008 and November 2010 (study areas first described by Pellew, 1983a): (1) Seronera (240 km2); (2) Kirawira (210 km2); (3) Bologonja (175 km2, sampled only in 2010). Study area comparisons focus on the well-sampled areas of Seronera and Kirawira. While giraffe density is similar in these areas (Strauss, unpubl. data), Kirawira has a lower lion density than Seronera (Packer, 1990; Mosser et al., 2009; A. Kittle, pers. comm., 2012) and high year-round densities of preferred lion prey such as wildebeest Connochaetes taurinus and topi Damaliscus lunatus.

We observed significant variations of serum sphingolipids with sphingosine and sphinganine being both in univariate (P<0.05) as well as in multivariate analysis significantly associated to http://www.selleckchem.com/products/ly2157299.html severity of liver fibrosis

in HCV infected patients (odds ratio (OR)=1.111, confidence interval (CI)=1.028-1.202, P=0.007 and OR=0.634, CI=0.435-0.925, P=0.018 respectively). Serum sphingolipids correlated significantly with serum triglyceride and cholesterol levels as well as with insulin resistance, defined by the homeostatic model assessment-index in HCV patients. Sustained viral response rates in HCV patients were independently predicted by serum C24ceramide (OR=0.998, CI=0.997-0.999, P=0.001), its unsaturated derivative C24:1ceramide (OR=1.001, CI=1.000-1.002, P=0.059) and C18:1ceramide (OR=0.973, CI=0.947-0.999, P=0.048) together with ferritin (OR=1.006, CI=1.003-1.010, P<0.001), alkaline phosphatase (AP) (OR=1.020, CI=1.001-1.039, P=0.032) and IL28B genotype (OR=9.483, CI=3.139-28.643, P<0.001). Conclusion: Our study demonstrates a tight interaction between variations in serum sphingolipid levels and progression of liver fibrosis as well as

responsiveness to antiviral therapy. FDA-approved Drug Library supplier Particularly sphingosine, sphinganine and C24ceramide appear as promising novel biomarkers in chronic HCV infection and should be further evaluated within the non-invasive prediction of liver fibrosis. (Hepatology 2014;) “
“Davila et al. showed that 17% of the patients older than 65 years with cirrhosis underwent regular screening for hepatocellular carcinoma (HCC), in whom only 54% had only an ultrasound procedure. Gastroenterologists were more likely (4.5-fold) than primary care physicians to perform regular surveillance.1 Hepatologist associations recommended that “patients at high risk for developing hepatocellular carcinoma should be entered into surveillance programs (Level I)”.2 However, only inconclusive or negative observational studies are available. Trevisani et al. concluded that screening improved survival (5 months) 上海皓元 despite

raw data showing that screened patients died 18 months younger than nonscreened patients (length of time and lead time biases)!3, 4 Other examples are available: Kemp et al. reported a 26-month increase in survival in screened versus incidentally discovered HCC, but screened patients were 3 years younger.5, 6 Recently, I reviewed a large series with similar biases and the authors refused to resubmit a revised version against screening. The National Cancer Institute wisely stated (last revision on April 3, 2008) that “based on fair evidence, screening would not result in a decrease in mortality from HCC … based on fair evidence, screening would result in rare but serious side effects (Study Design: Randomized controlled trials and observational studies. Internal validity: Fair. Consistency: Multiple studies, large number of participants. External validity: Good/Fair.)”.

We observed significant variations of serum sphingolipids with sphingosine and sphinganine being both in univariate (P<0.05) as well as in multivariate analysis significantly associated to FK506 severity of liver fibrosis

in HCV infected patients (odds ratio (OR)=1.111, confidence interval (CI)=1.028-1.202, P=0.007 and OR=0.634, CI=0.435-0.925, P=0.018 respectively). Serum sphingolipids correlated significantly with serum triglyceride and cholesterol levels as well as with insulin resistance, defined by the homeostatic model assessment-index in HCV patients. Sustained viral response rates in HCV patients were independently predicted by serum C24ceramide (OR=0.998, CI=0.997-0.999, P=0.001), its unsaturated derivative C24:1ceramide (OR=1.001, CI=1.000-1.002, P=0.059) and C18:1ceramide (OR=0.973, CI=0.947-0.999, P=0.048) together with ferritin (OR=1.006, CI=1.003-1.010, P<0.001), alkaline phosphatase (AP) (OR=1.020, CI=1.001-1.039, P=0.032) and IL28B genotype (OR=9.483, CI=3.139-28.643, P<0.001). Conclusion: Our study demonstrates a tight interaction between variations in serum sphingolipid levels and progression of liver fibrosis as well as

responsiveness to antiviral therapy. ABC294640 Particularly sphingosine, sphinganine and C24ceramide appear as promising novel biomarkers in chronic HCV infection and should be further evaluated within the non-invasive prediction of liver fibrosis. (Hepatology 2014;) “
“Davila et al. showed that 17% of the patients older than 65 years with cirrhosis underwent regular screening for hepatocellular carcinoma (HCC), in whom only 54% had only an ultrasound procedure. Gastroenterologists were more likely (4.5-fold) than primary care physicians to perform regular surveillance.1 Hepatologist associations recommended that “patients at high risk for developing hepatocellular carcinoma should be entered into surveillance programs (Level I)”.2 However, only inconclusive or negative observational studies are available. Trevisani et al. concluded that screening improved survival (5 months) MCE公司 despite

raw data showing that screened patients died 18 months younger than nonscreened patients (length of time and lead time biases)!3, 4 Other examples are available: Kemp et al. reported a 26-month increase in survival in screened versus incidentally discovered HCC, but screened patients were 3 years younger.5, 6 Recently, I reviewed a large series with similar biases and the authors refused to resubmit a revised version against screening. The National Cancer Institute wisely stated (last revision on April 3, 2008) that “based on fair evidence, screening would not result in a decrease in mortality from HCC … based on fair evidence, screening would result in rare but serious side effects (Study Design: Randomized controlled trials and observational studies. Internal validity: Fair. Consistency: Multiple studies, large number of participants. External validity: Good/Fair.)”.

His successful academic career started at Harvard Medical School in 1961 and proceeded until becoming Professor of Medicine at Northwestern University Medical School, Chicago, IL. After retirement in 1995, he spent 3 years in Amsterdam, NL to then move to Seattle to be appointed Affiliated Professor of Medicine at the University of Washington

where he was actively involved in research and preparing teaching material for a highly appreciated GE course. Dr. Ostrow served as president of the American Association for the Study of Liver Diseases in 1986-1987. Don Ostrow has been and will remain a giant in the field of bilirubin and jaundice. He was among the few persons who understood back in the 1960s the importance MK-1775 cost SB431542 order and the pivotal role of the yellow pigment until then considered only as a waste product. Due to his unmatched scientific curiosity, Don realized that bilirubin might have important biological functions crucial to several metabolic pathways. Almost all of these theories have been proven correct as more advanced experimental techniques became available. Taking advantage of his scientific background in both chemistry and medicine, Don combined this dual physical chemical and clinical approach to the study of bilirubin. His unique discoveries made Don one of the first real translational researchers

in hepatology. The determination of the solubility of bilirubin in aqueous media, the binding constants to albumin, and their role in the metabolic and toxic effects of the pigment shed totally new light on bilirubin neurotoxicity in the newborn and paved the

way to more sophisticated investigations aimed at understanding the molecular events associated with the neurotoxicity and therefore its prevention. His contributions to the chemical and biological characteristics of bilirubin will remain landmarks for anyone involved in the study of the pigment, either in the experimental or clinical arena. The translational approach in medicine, rather new back in 1960s and 1970s, made his laboratory the place to be for young fellows to be trained and share front-row studies of the correlation between the chemical structure and the biological behavior of bilirubin and bile acids. Anyone who had MCE公司 the privilege to work with Don admired his analytic mind, his ability to interpret experimental data, to criticize experimental flaws, and to put new observations in perspective. This was particularly true when Don discussed science with young investigators—a tough mentor who could issue sharp critiques but at the same time precious suggestions and encouragement to continue what she/he was doing. The ability to grasp the critical points after a complicated presentation of sophisticated molecular biology data was remarkable.

His successful academic career started at Harvard Medical School in 1961 and proceeded until becoming Professor of Medicine at Northwestern University Medical School, Chicago, IL. After retirement in 1995, he spent 3 years in Amsterdam, NL to then move to Seattle to be appointed Affiliated Professor of Medicine at the University of Washington

where he was actively involved in research and preparing teaching material for a highly appreciated GE course. Dr. Ostrow served as president of the American Association for the Study of Liver Diseases in 1986-1987. Don Ostrow has been and will remain a giant in the field of bilirubin and jaundice. He was among the few persons who understood back in the 1960s the importance find more Lorlatinib nmr and the pivotal role of the yellow pigment until then considered only as a waste product. Due to his unmatched scientific curiosity, Don realized that bilirubin might have important biological functions crucial to several metabolic pathways. Almost all of these theories have been proven correct as more advanced experimental techniques became available. Taking advantage of his scientific background in both chemistry and medicine, Don combined this dual physical chemical and clinical approach to the study of bilirubin. His unique discoveries made Don one of the first real translational researchers

in hepatology. The determination of the solubility of bilirubin in aqueous media, the binding constants to albumin, and their role in the metabolic and toxic effects of the pigment shed totally new light on bilirubin neurotoxicity in the newborn and paved the

way to more sophisticated investigations aimed at understanding the molecular events associated with the neurotoxicity and therefore its prevention. His contributions to the chemical and biological characteristics of bilirubin will remain landmarks for anyone involved in the study of the pigment, either in the experimental or clinical arena. The translational approach in medicine, rather new back in 1960s and 1970s, made his laboratory the place to be for young fellows to be trained and share front-row studies of the correlation between the chemical structure and the biological behavior of bilirubin and bile acids. Anyone who had medchemexpress the privilege to work with Don admired his analytic mind, his ability to interpret experimental data, to criticize experimental flaws, and to put new observations in perspective. This was particularly true when Don discussed science with young investigators—a tough mentor who could issue sharp critiques but at the same time precious suggestions and encouragement to continue what she/he was doing. The ability to grasp the critical points after a complicated presentation of sophisticated molecular biology data was remarkable.

His successful academic career started at Harvard Medical School in 1961 and proceeded until becoming Professor of Medicine at Northwestern University Medical School, Chicago, IL. After retirement in 1995, he spent 3 years in Amsterdam, NL to then move to Seattle to be appointed Affiliated Professor of Medicine at the University of Washington

where he was actively involved in research and preparing teaching material for a highly appreciated GE course. Dr. Ostrow served as president of the American Association for the Study of Liver Diseases in 1986-1987. Don Ostrow has been and will remain a giant in the field of bilirubin and jaundice. He was among the few persons who understood back in the 1960s the importance INK 128 purchase DAPT molecular weight and the pivotal role of the yellow pigment until then considered only as a waste product. Due to his unmatched scientific curiosity, Don realized that bilirubin might have important biological functions crucial to several metabolic pathways. Almost all of these theories have been proven correct as more advanced experimental techniques became available. Taking advantage of his scientific background in both chemistry and medicine, Don combined this dual physical chemical and clinical approach to the study of bilirubin. His unique discoveries made Don one of the first real translational researchers

in hepatology. The determination of the solubility of bilirubin in aqueous media, the binding constants to albumin, and their role in the metabolic and toxic effects of the pigment shed totally new light on bilirubin neurotoxicity in the newborn and paved the

way to more sophisticated investigations aimed at understanding the molecular events associated with the neurotoxicity and therefore its prevention. His contributions to the chemical and biological characteristics of bilirubin will remain landmarks for anyone involved in the study of the pigment, either in the experimental or clinical arena. The translational approach in medicine, rather new back in 1960s and 1970s, made his laboratory the place to be for young fellows to be trained and share front-row studies of the correlation between the chemical structure and the biological behavior of bilirubin and bile acids. Anyone who had medchemexpress the privilege to work with Don admired his analytic mind, his ability to interpret experimental data, to criticize experimental flaws, and to put new observations in perspective. This was particularly true when Don discussed science with young investigators—a tough mentor who could issue sharp critiques but at the same time precious suggestions and encouragement to continue what she/he was doing. The ability to grasp the critical points after a complicated presentation of sophisticated molecular biology data was remarkable.

These effects

were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. Conclusion: We have identified a relationship between HCV and Hh signaling where RG7204 mw up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics. (HEPATOLOGY 2011;) Hepatitis C virus (HCV) is an important cause of chronic liver disease, with the severe consequences of

hepatocellular carcinoma (HCC) and cirrhosis occurring in some patients.1, 2 When considering determinants of HCV persistence and propagation of infection, little consideration has been given to differences between cells within the liver. Recent studies have demonstrated HCV Core protein localized to discrete foci within HCC sections from patients, and laser captured microdissection samples indicated that HCV genomes exist at unexpectedly low average copy numbers per cell.3, 4 These observations suggest that HCV infection is not widespread throughout the liver, but rather selective or restrained in its target cells. In vitro studies of HCV rely heavily on the Huh7.5 cell line. This cell line was generated after Huh7 cells selected for harboring an HCV subgenomic replicon were cured of replicating viral RNA with interferon-α.5 Dasatinib The resulting cells were highly permissive for HCV replication when retransfected with replicon constructs. As they support replication of the JFH1 viral isolate and produce infectious virus in tissue culture, Huh7.5 cells have propelled studies of the HCV life-cycle forward.6 Similar cell lines with increased HCV permissivity, medchemexpress like LH86 cells, have been directly isolated from patient

samples, although HCV RNA levels are 1-2 log lower compared with Huh7.5 cells.7 The reasons for Huh7.5 cells being exceptionally permissive for HCV replication were attributed to a defect in RIG-I, a pattern recognition receptor that activates type I interferon expression during viral infection.8 However, recent studies found no RIG-I defects in novel cell lines also generated from Huh7 cells with increased permissiveness to HCV.9, 10 Thus, RIG-I alone may not explain this phenomenon. The Hedgehog (Hh) pathway plays an important role during embryogenesis, normal tissue growth, regeneration after injury, and carcinogenesis.11-15 Most hepatocytes in healthy adult livers do not express detectable Hh ligands Sonic hedgehog (Shh) or Indian hedgehog (Ihh), whereas some Hh ligand expression can be demonstrated in ductular-type cells.

These effects

were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. Conclusion: We have identified a relationship between HCV and Hh signaling where GW 572016 up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics. (HEPATOLOGY 2011;) Hepatitis C virus (HCV) is an important cause of chronic liver disease, with the severe consequences of

hepatocellular carcinoma (HCC) and cirrhosis occurring in some patients.1, 2 When considering determinants of HCV persistence and propagation of infection, little consideration has been given to differences between cells within the liver. Recent studies have demonstrated HCV Core protein localized to discrete foci within HCC sections from patients, and laser captured microdissection samples indicated that HCV genomes exist at unexpectedly low average copy numbers per cell.3, 4 These observations suggest that HCV infection is not widespread throughout the liver, but rather selective or restrained in its target cells. In vitro studies of HCV rely heavily on the Huh7.5 cell line. This cell line was generated after Huh7 cells selected for harboring an HCV subgenomic replicon were cured of replicating viral RNA with interferon-α.5 Temozolomide manufacturer The resulting cells were highly permissive for HCV replication when retransfected with replicon constructs. As they support replication of the JFH1 viral isolate and produce infectious virus in tissue culture, Huh7.5 cells have propelled studies of the HCV life-cycle forward.6 Similar cell lines with increased HCV permissivity, MCE like LH86 cells, have been directly isolated from patient

samples, although HCV RNA levels are 1-2 log lower compared with Huh7.5 cells.7 The reasons for Huh7.5 cells being exceptionally permissive for HCV replication were attributed to a defect in RIG-I, a pattern recognition receptor that activates type I interferon expression during viral infection.8 However, recent studies found no RIG-I defects in novel cell lines also generated from Huh7 cells with increased permissiveness to HCV.9, 10 Thus, RIG-I alone may not explain this phenomenon. The Hedgehog (Hh) pathway plays an important role during embryogenesis, normal tissue growth, regeneration after injury, and carcinogenesis.11-15 Most hepatocytes in healthy adult livers do not express detectable Hh ligands Sonic hedgehog (Shh) or Indian hedgehog (Ihh), whereas some Hh ligand expression can be demonstrated in ductular-type cells.

28 Interestingly, considering only noninvasive parameters, the AUC of the model that includes vitamin D levels to predict severe fibrosis remains good. This suggests the potential use of serum 25(OH)D levels as a noninvasive marker

of liver fibrosis, a use that needs to be tested and validated in large prospective cohort studies in patients with CHC of all genotypes, and in chronic liver disease of other origins. It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis. Different experimental models showed that vitamin D, selleck screening library via interaction with vitamin D receptor, protects against oxidative stress production,29 can influence the migration, proliferation, and gene expression of fibroblasts,30, 31 and reduces the inflammatory

and fibrogenic activity of liver stellate cells.32, 33 However further prospective cohort studies will selleck compound be needed to determine the causal association between vitamin D deficiency and fibrosis in patients with CHC. Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR. Again, this observation will require further validation in different, large cohorts of patients, but is supported by experimental data that suggest a role of vitamin D in the modulation of the immune response,32, 33 and by recent clinical data36 reporting higher early virological response rate in CHC treated with standard of care plus vitamin D, compared with those treated with standard of care only. Finally, in line with data from the literature, we found that steatosis35 and lower cholesterol levels, a known surrogate marker of fibrosis severity,26 were independently associated with lower SVR rate. We did not find any association MCE between IR and SVR, in keeping the conflicting data reported in the literature on the role of IR as a predictor of SVR.36 The main limitation of this study lies in its cross-sectional nature and its inability to dissect the temporal relation between 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different

populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake, and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant, even if we cannot rule out differences in sun exposure between healthy controls and CHC patients. However, data on the prevalence of osteoporosis were not available, nor was the dietary intake of vitamin D, which, however, remains a rather crude measure of vitamin D status because of recall bias. The lack of these data in both cases and controls makes a systematic error very unlikely. Also, data on osteoporosis were not available in both groups.

28 Interestingly, considering only noninvasive parameters, the AUC of the model that includes vitamin D levels to predict severe fibrosis remains good. This suggests the potential use of serum 25(OH)D levels as a noninvasive marker

of liver fibrosis, a use that needs to be tested and validated in large prospective cohort studies in patients with CHC of all genotypes, and in chronic liver disease of other origins. It is conceivable that a reduced 25(OH)D level might by itself favor progression of fibrosis. Different experimental models showed that vitamin D, LY2157299 ic50 via interaction with vitamin D receptor, protects against oxidative stress production,29 can influence the migration, proliferation, and gene expression of fibroblasts,30, 31 and reduces the inflammatory

and fibrogenic activity of liver stellate cells.32, 33 However further prospective cohort studies will buy Neratinib be needed to determine the causal association between vitamin D deficiency and fibrosis in patients with CHC. Another interesting finding of this study is the evidence that lower 25(OH)D serum levels were an independent negative risk factor for SVR. Again, this observation will require further validation in different, large cohorts of patients, but is supported by experimental data that suggest a role of vitamin D in the modulation of the immune response,32, 33 and by recent clinical data36 reporting higher early virological response rate in CHC treated with standard of care plus vitamin D, compared with those treated with standard of care only. Finally, in line with data from the literature, we found that steatosis35 and lower cholesterol levels, a known surrogate marker of fibrosis severity,26 were independently associated with lower SVR rate. We did not find any association medchemexpress between IR and SVR, in keeping the conflicting data reported in the literature on the role of IR as a predictor of SVR.36 The main limitation of this study lies in its cross-sectional nature and its inability to dissect the temporal relation between 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different

populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake, and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant, even if we cannot rule out differences in sun exposure between healthy controls and CHC patients. However, data on the prevalence of osteoporosis were not available, nor was the dietary intake of vitamin D, which, however, remains a rather crude measure of vitamin D status because of recall bias. The lack of these data in both cases and controls makes a systematic error very unlikely. Also, data on osteoporosis were not available in both groups.