A larger follow-up of the cohort will definitely rule out or confirm if LS also predicts overall mortality. Other prognostic factors found in this study were hepatitis B coinfection, high HCV RNA viral load, GDC-0973 concentration and CTP score. Also, MELD score predicted the development of liver events

but its independent predictive value could not be assessed as a statistical interaction with CTP stage was found. Interestingly, MELD score was associated with overall mortality but not with liver-related mortality after multivariate analyses in our study. In fact, the predictive value of MELD score in HIV/HCV-coinfected patients remains controversial, with previous studies reporting no independent association with survival6, 33 and others finding such an association.34, 35 In our opinion, the lack of an independent association of MELD with liver-related mortality in our cohort could reflect a weaker CYC202 chemical structure predictive value in the long term, as is the case in this study, than in the short- and mid-term. Achievement of SVR after treatment of hepatitis C is associated with a reduction in liver-related mortality in HIV-negative36 and HIV-positive patients.37 The impact of anti-HCV therapy on the survival or the risk of decompensations

in HIV/HCV-coinfected patients with compensated cirrhosis has been only assessed in two previous cohort studies with apparent conflicting data.33, 38 In the present study, neither exposure to HCV therapy nor achieving SVR during follow-up were associated with a lower risk of developing decompensations. On the contrary, achieving

SVR during follow-up tended to be associated with an improved survival in univariate analyses and exposure to therapy during follow-up was associated with a lower risk of death of any cause. However, these associations did not reach statistical significance, probably due to lack of power and insufficient follow-up. Finally, previous exposure to HCV therapy before enrolment was associated with increased mortality. In our opinion, this association probably reflects a longer time of evolution and an advanced stage of liver disease selleckchem in previous nonresponder patients rather than a worrisome effect of therapy. Additionally, we cannot definitely exclude that selection bias of patients who received prior HCV therapy may have affected our results. Our study may have some limitations. The follow-up period was somewhat short, and the number of some events, particularly liver-related deaths, was relatively low. This might have precluded identifying some potential predictors of mortality as the consecution of SVR. However, the follow-up was long enough to identify other stronger predictors of clinical outcomes such as CTP score or HBV coinfection.

A larger follow-up of the cohort will definitely rule out or confirm if LS also predicts overall mortality. Other prognostic factors found in this study were hepatitis B coinfection, high HCV RNA viral load, ABT-263 cost and CTP score. Also, MELD score predicted the development of liver events

but its independent predictive value could not be assessed as a statistical interaction with CTP stage was found. Interestingly, MELD score was associated with overall mortality but not with liver-related mortality after multivariate analyses in our study. In fact, the predictive value of MELD score in HIV/HCV-coinfected patients remains controversial, with previous studies reporting no independent association with survival6, 33 and others finding such an association.34, 35 In our opinion, the lack of an independent association of MELD with liver-related mortality in our cohort could reflect a weaker selleck inhibitor predictive value in the long term, as is the case in this study, than in the short- and mid-term. Achievement of SVR after treatment of hepatitis C is associated with a reduction in liver-related mortality in HIV-negative36 and HIV-positive patients.37 The impact of anti-HCV therapy on the survival or the risk of decompensations

in HIV/HCV-coinfected patients with compensated cirrhosis has been only assessed in two previous cohort studies with apparent conflicting data.33, 38 In the present study, neither exposure to HCV therapy nor achieving SVR during follow-up were associated with a lower risk of developing decompensations. On the contrary, achieving

SVR during follow-up tended to be associated with an improved survival in univariate analyses and exposure to therapy during follow-up was associated with a lower risk of death of any cause. However, these associations did not reach statistical significance, probably due to lack of power and insufficient follow-up. Finally, previous exposure to HCV therapy before enrolment was associated with increased mortality. In our opinion, this association probably reflects a longer time of evolution and an advanced stage of liver disease learn more in previous nonresponder patients rather than a worrisome effect of therapy. Additionally, we cannot definitely exclude that selection bias of patients who received prior HCV therapy may have affected our results. Our study may have some limitations. The follow-up period was somewhat short, and the number of some events, particularly liver-related deaths, was relatively low. This might have precluded identifying some potential predictors of mortality as the consecution of SVR. However, the follow-up was long enough to identify other stronger predictors of clinical outcomes such as CTP score or HBV coinfection.

To further address this interesting and important issue, the authors could provide data for analysis about viral load decline and the amount of weight loss at week 24 of therapy. In summary, several potentially effective agents have

been added to improve the SVR rate in difficult-to-cure patients with chronic hepatitis C. These agents include protease inhibitors to increase the antiviral effect5 or insulin sensitizers to increase insulin sensitivity. In addition, the optimal dose of ribavirin should be carefully adjusted on the basis of body weight and with adverse effects in mind, to achieve the highest possible SVR rate. However, further studies are still needed to optimize the combination regimens with currently available agents. Chia-Chi Wang M.D.*, Jia-Horng Kao Ph.D.†, * Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University,

buy PI3K Inhibitor Library Hualien, Taiwan, DMXAA manufacturer † Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. “
“Mucosa-associated lymphoid tissue (MALT) lymphoma derived from the B-lymphocytes, rarely occurs in the gastrointestinal (GI) tract. The commonest site of occurrence is the stomach. Narrow band imaging (NBI) with magnifying endoscopy can identify MALT lymphoma and there have been several reports and case series on this. We presently report a 79-year-old man who underwent GI endoscopy as part of a health checkup. Conventional see more endoscopy showed a depressed reddish lesion in the posterior wall of the mid-gastric body (Figure 1A). Chromoendoscopy with indigo carmine identified this to be a depressed lesion. (Figure 1B) Magnifying endoscopy with NBI showed a cleare demarcation line of this depressed lesion (Figure 1C, arrows), and revealed an loss of the normal epithelium and abnormal micro-vessels that did not have the typical tree-branching calibre changes around white round lesions

(Figure 1D). Endoscopic biopsy specimens taken from the lesion showed a diffuse proliferation of abnormal lymphoid cells within the mucosa (low-power histology—not shown). High-power histology showed a diffuse proliferation of small centrocyte-like cells and lymphoepithelial lesions. Immunohistochemical analysis was positive for CD20 but negative for CD3. He was diagnosed as having gastric MALT lymphoma. The positron-emission tomography/computed tomography showed only gastric uptake and no other extra-nodal disease. Based on the histopathological findings, a diagnosis of gastric MALT lymphoma (high-grade) was made, and combination-chemotherapy with pirarubicin hydrochloride, cyclophosphamide, vincristine sulfate and rituximab was started. Contributed by “
“A woman, aged 65, was admitted to hospital for review of cancer management. Ten years previously, she had undergone a radical mastectomy for breast cancer.

To further address this interesting and important issue, the authors could provide data for analysis about viral load decline and the amount of weight loss at week 24 of therapy. In summary, several potentially effective agents have

been added to improve the SVR rate in difficult-to-cure patients with chronic hepatitis C. These agents include protease inhibitors to increase the antiviral effect5 or insulin sensitizers to increase insulin sensitivity. In addition, the optimal dose of ribavirin should be carefully adjusted on the basis of body weight and with adverse effects in mind, to achieve the highest possible SVR rate. However, further studies are still needed to optimize the combination regimens with currently available agents. Chia-Chi Wang M.D.*, Jia-Horng Kao Ph.D.†, * Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University,

Alvelestat cell line Hualien, Taiwan, selleck chemicals llc † Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. “
“Mucosa-associated lymphoid tissue (MALT) lymphoma derived from the B-lymphocytes, rarely occurs in the gastrointestinal (GI) tract. The commonest site of occurrence is the stomach. Narrow band imaging (NBI) with magnifying endoscopy can identify MALT lymphoma and there have been several reports and case series on this. We presently report a 79-year-old man who underwent GI endoscopy as part of a health checkup. Conventional selleck kinase inhibitor endoscopy showed a depressed reddish lesion in the posterior wall of the mid-gastric body (Figure 1A). Chromoendoscopy with indigo carmine identified this to be a depressed lesion. (Figure 1B) Magnifying endoscopy with NBI showed a cleare demarcation line of this depressed lesion (Figure 1C, arrows), and revealed an loss of the normal epithelium and abnormal micro-vessels that did not have the typical tree-branching calibre changes around white round lesions

(Figure 1D). Endoscopic biopsy specimens taken from the lesion showed a diffuse proliferation of abnormal lymphoid cells within the mucosa (low-power histology—not shown). High-power histology showed a diffuse proliferation of small centrocyte-like cells and lymphoepithelial lesions. Immunohistochemical analysis was positive for CD20 but negative for CD3. He was diagnosed as having gastric MALT lymphoma. The positron-emission tomography/computed tomography showed only gastric uptake and no other extra-nodal disease. Based on the histopathological findings, a diagnosis of gastric MALT lymphoma (high-grade) was made, and combination-chemotherapy with pirarubicin hydrochloride, cyclophosphamide, vincristine sulfate and rituximab was started. Contributed by “
“A woman, aged 65, was admitted to hospital for review of cancer management. Ten years previously, she had undergone a radical mastectomy for breast cancer.

1). Reinfection or superinfection with a different virus from the same subtype (e.g., 1a-1a) was designated when the nucleotide divergence was above the minimum value plus 3× SD (6.0%) for viruses within each subtype (range, 2.4%-13.4%; mean ± SD, 8.7% ± 1.2%) (Fig. 1). Sequence divergence of viruses from different subtypes (e.g.,

1a-1b) ranged from 20.1% to 28.2% (mean ± SD, 23.4% ± 1.0%) and of viruses from different genotypes (e.g., 1a-3a) ranged from 28.9% to 39.0%; (mean ± SD, 32.6% ± 1.5%) (Fig. 1). The estimated duration of mixed infection was calculated using the midpoint between the initial mixed incident infection time point and the subsequent resolution to a single HCV strain. The estimated time

to infection with a second virus following a primary infection was calculated as the interval between incident HCV detection and initial detection of the www.selleckchem.com/products/Nolvadex.html multiple infection (mixed superinfection, reinfection, or strain switch). The incidence of multiple infection was calculated as the person-years rate of new infections with all subjects contributing follow-up time from initial incident HCV detection and censored at last HCV RNA time point. Subjects were not censored at detection of multiple infection, because further cases of multiple infection within individual subjects were possible. Analysis of the first 488 previously anti-HCV antibody–seronegative NVP-BKM120 solubility dmso subjects enrolled in the HITS cohort indicated that the population was predominantly male (65%), with high rates of prior selleck compound imprisonment (72%) and longstanding injection drug use (mean 8.5 years). During a mean follow-up of 38 ± 33 weeks, a total of 90 incident HCV infections were detected, including 87 (96.7%) subjects with detectable HCV RNA sequences at initial infection. Of these 87 subjects, 48 completed at least one further longitudinal time point following detection of incident HCV infection (Fig. 2). Eighty-seven incident HCV infection cases who had viral sequences available were analyzed for

multiple infection, with an average of 16 ± 28 weeks since the last undetectable HCV RNA sample (range, 0-127 weeks). Nine of 87 (10.3%) subjects were designated as incident cases of mixed infection, because two distinct HCV strains were detected at the first HCV RNA–detectable time point (Figs. 2 and 3). These observed mixed incident infections included 1a-3a (n = 4), 1a-2a (n = 2), 2a-3a (n = 1), 1b-2b (n = 1), and 3a-3a (11.0% divergence) (n = 1) (Fig. 3A). Core and/or E1/HVR1 sequences were generated for all follow-up time points available for 48 of 87 subjects (mean sampling interval, 26 ± 29 weeks) (two time points, n = 18; three time points, n = 10; four time points, n = 12; five or more time points, n = 8). Fifteen of the 48 subjects became infected with a new HCV strain during follow-up (cumulative prevalence of subsequent infection, 31.3%) (Figs. 2 and 3).

1). Reinfection or superinfection with a different virus from the same subtype (e.g., 1a-1a) was designated when the nucleotide divergence was above the minimum value plus 3× SD (6.0%) for viruses within each subtype (range, 2.4%-13.4%; mean ± SD, 8.7% ± 1.2%) (Fig. 1). Sequence divergence of viruses from different subtypes (e.g.,

1a-1b) ranged from 20.1% to 28.2% (mean ± SD, 23.4% ± 1.0%) and of viruses from different genotypes (e.g., 1a-3a) ranged from 28.9% to 39.0%; (mean ± SD, 32.6% ± 1.5%) (Fig. 1). The estimated duration of mixed infection was calculated using the midpoint between the initial mixed incident infection time point and the subsequent resolution to a single HCV strain. The estimated time

to infection with a second virus following a primary infection was calculated as the interval between incident HCV detection and initial detection of the selleck chemicals multiple infection (mixed superinfection, reinfection, or strain switch). The incidence of multiple infection was calculated as the person-years rate of new infections with all subjects contributing follow-up time from initial incident HCV detection and censored at last HCV RNA time point. Subjects were not censored at detection of multiple infection, because further cases of multiple infection within individual subjects were possible. Analysis of the first 488 previously anti-HCV antibody–seronegative www.selleckchem.com/products/AZD6244.html subjects enrolled in the HITS cohort indicated that the population was predominantly male (65%), with high rates of prior selleck compound imprisonment (72%) and longstanding injection drug use (mean 8.5 years). During a mean follow-up of 38 ± 33 weeks, a total of 90 incident HCV infections were detected, including 87 (96.7%) subjects with detectable HCV RNA sequences at initial infection. Of these 87 subjects, 48 completed at least one further longitudinal time point following detection of incident HCV infection (Fig. 2). Eighty-seven incident HCV infection cases who had viral sequences available were analyzed for

multiple infection, with an average of 16 ± 28 weeks since the last undetectable HCV RNA sample (range, 0-127 weeks). Nine of 87 (10.3%) subjects were designated as incident cases of mixed infection, because two distinct HCV strains were detected at the first HCV RNA–detectable time point (Figs. 2 and 3). These observed mixed incident infections included 1a-3a (n = 4), 1a-2a (n = 2), 2a-3a (n = 1), 1b-2b (n = 1), and 3a-3a (11.0% divergence) (n = 1) (Fig. 3A). Core and/or E1/HVR1 sequences were generated for all follow-up time points available for 48 of 87 subjects (mean sampling interval, 26 ± 29 weeks) (two time points, n = 18; three time points, n = 10; four time points, n = 12; five or more time points, n = 8). Fifteen of the 48 subjects became infected with a new HCV strain during follow-up (cumulative prevalence of subsequent infection, 31.3%) (Figs. 2 and 3).

1). Reinfection or superinfection with a different virus from the same subtype (e.g., 1a-1a) was designated when the nucleotide divergence was above the minimum value plus 3× SD (6.0%) for viruses within each subtype (range, 2.4%-13.4%; mean ± SD, 8.7% ± 1.2%) (Fig. 1). Sequence divergence of viruses from different subtypes (e.g.,

1a-1b) ranged from 20.1% to 28.2% (mean ± SD, 23.4% ± 1.0%) and of viruses from different genotypes (e.g., 1a-3a) ranged from 28.9% to 39.0%; (mean ± SD, 32.6% ± 1.5%) (Fig. 1). The estimated duration of mixed infection was calculated using the midpoint between the initial mixed incident infection time point and the subsequent resolution to a single HCV strain. The estimated time

to infection with a second virus following a primary infection was calculated as the interval between incident HCV detection and initial detection of the check details multiple infection (mixed superinfection, reinfection, or strain switch). The incidence of multiple infection was calculated as the person-years rate of new infections with all subjects contributing follow-up time from initial incident HCV detection and censored at last HCV RNA time point. Subjects were not censored at detection of multiple infection, because further cases of multiple infection within individual subjects were possible. Analysis of the first 488 previously anti-HCV antibody–seronegative selleck kinase inhibitor subjects enrolled in the HITS cohort indicated that the population was predominantly male (65%), with high rates of prior find more imprisonment (72%) and longstanding injection drug use (mean 8.5 years). During a mean follow-up of 38 ± 33 weeks, a total of 90 incident HCV infections were detected, including 87 (96.7%) subjects with detectable HCV RNA sequences at initial infection. Of these 87 subjects, 48 completed at least one further longitudinal time point following detection of incident HCV infection (Fig. 2). Eighty-seven incident HCV infection cases who had viral sequences available were analyzed for

multiple infection, with an average of 16 ± 28 weeks since the last undetectable HCV RNA sample (range, 0-127 weeks). Nine of 87 (10.3%) subjects were designated as incident cases of mixed infection, because two distinct HCV strains were detected at the first HCV RNA–detectable time point (Figs. 2 and 3). These observed mixed incident infections included 1a-3a (n = 4), 1a-2a (n = 2), 2a-3a (n = 1), 1b-2b (n = 1), and 3a-3a (11.0% divergence) (n = 1) (Fig. 3A). Core and/or E1/HVR1 sequences were generated for all follow-up time points available for 48 of 87 subjects (mean sampling interval, 26 ± 29 weeks) (two time points, n = 18; three time points, n = 10; four time points, n = 12; five or more time points, n = 8). Fifteen of the 48 subjects became infected with a new HCV strain during follow-up (cumulative prevalence of subsequent infection, 31.3%) (Figs. 2 and 3).

Relative expression was determined by comparison of dT values relative to glyceraldehyde 3-phosphate dehydrogenase expression using the 2-ΔΔCT method. Single liver cell suspensions

were prepared by mincing and passing over 40 μm cell strainers Erismodegib in vitro (Fisher Scientific, Pittsburgh, PA). After centrifugation at 2,000 rpm, a cell pellet was mixed with 33% Percoll (Sigma-Aldrich, St. Louis, MO) in RPMI 1640 solution (Invitrogen, Carlsbad, CA). Cell suspension was centrifuged at 2,000 rpm for 20 minutes at room temperature, the cell pellet was removed and washed, and red blood cells were lysed with 1× lysis buffer (eBioscience, San Diego, CA). Cells were suspended in 50 μL fluorescence-activated cell sorting buffer and Fc receptor was blocked with anti-mouse CD16/32 (clone 93, eBioscience). Cells were stained with CD11b-PerCP-Cy5.5 (clone M1/70), F4/80-PE (clone BM8), and Gr1-FITC (clone 1A8) (eBioscience). Cells were acquired on a FacsCanto FlowCytometer (BD Biosciences, San Jose, CA) and data were analyzed NVP-BEZ235 chemical structure using FlowJo software version 7.5 (TreeStar, Ashland, OR). Frozen liver sections were rehydrated in phosphate-buffered saline (PBS). Stock dihydroethidium (DHE) (Sigma-Aldrich) solution was diluted in dimethyl sulfoxide (Sigma-Aldrich). Slides were incubated in DHE

solution and washed with 1× phosphate-buffered saline and placed on coverslips using 80% glycerol in phosphate-buffered saline. Fluorescence was recorded and quantified using Texas red filter on an upright Olympus BX51 microscope using DPControler software (Olympus, Hamburg, Germany) and IMAGE J software (National Institutes of Health, Bethesda, MD).34 Liver sections were incubated in 10% normal horse serum after blocking. Sections were incubated with the 4-hydroxynonenal primary antibody (Alpha Diagnostic International, San Antonio, TX) overnight and then incubated with secondary biotin conjugated antibody (Alpha Diagnostic International). Avidin–biotin peroxidase complex (Vector Laboratories, Burlingame, CA) staining was performed with diaminobenzidine

(Vector Laboratories). The sections were counterstained with Mayer’s hematoxylin. Quantification of CoQ9 was performed as described.35 Plasma with internal standard CoQ11 was injected into an automated high-performance liquid chromatographic system equipped with a coulometer detector. see more Quantification of oxCoQ9 was obtained using ChromQuest software (Fisher Scientific, Pittsburgh, PA). After injection, the extract was mixed with 1,4-benzoquinone, incubated, and then injected into the high-performance liquid chromatographic system for measuring total CoQ9. Concentration of reduced coenzyme Q9 was achieved by subtracting oxCoQ9 from total CoQ9. Statistical comparison between groups and treatments was performed using one-way analysis of variance (ANOVA) and post hoc Tukey’s test. Student t tests were used when comparing two groups. A P value of <0.05 was considered statistically significant.

Relative expression was determined by comparison of dT values relative to glyceraldehyde 3-phosphate dehydrogenase expression using the 2-ΔΔCT method. Single liver cell suspensions

were prepared by mincing and passing over 40 μm cell strainers selleck products (Fisher Scientific, Pittsburgh, PA). After centrifugation at 2,000 rpm, a cell pellet was mixed with 33% Percoll (Sigma-Aldrich, St. Louis, MO) in RPMI 1640 solution (Invitrogen, Carlsbad, CA). Cell suspension was centrifuged at 2,000 rpm for 20 minutes at room temperature, the cell pellet was removed and washed, and red blood cells were lysed with 1× lysis buffer (eBioscience, San Diego, CA). Cells were suspended in 50 μL fluorescence-activated cell sorting buffer and Fc receptor was blocked with anti-mouse CD16/32 (clone 93, eBioscience). Cells were stained with CD11b-PerCP-Cy5.5 (clone M1/70), F4/80-PE (clone BM8), and Gr1-FITC (clone 1A8) (eBioscience). Cells were acquired on a FacsCanto FlowCytometer (BD Biosciences, San Jose, CA) and data were analyzed AUY-922 solubility dmso using FlowJo software version 7.5 (TreeStar, Ashland, OR). Frozen liver sections were rehydrated in phosphate-buffered saline (PBS). Stock dihydroethidium (DHE) (Sigma-Aldrich) solution was diluted in dimethyl sulfoxide (Sigma-Aldrich). Slides were incubated in DHE

solution and washed with 1× phosphate-buffered saline and placed on coverslips using 80% glycerol in phosphate-buffered saline. Fluorescence was recorded and quantified using Texas red filter on an upright Olympus BX51 microscope using DPControler software (Olympus, Hamburg, Germany) and IMAGE J software (National Institutes of Health, Bethesda, MD).34 Liver sections were incubated in 10% normal horse serum after blocking. Sections were incubated with the 4-hydroxynonenal primary antibody (Alpha Diagnostic International, San Antonio, TX) overnight and then incubated with secondary biotin conjugated antibody (Alpha Diagnostic International). Avidin–biotin peroxidase complex (Vector Laboratories, Burlingame, CA) staining was performed with diaminobenzidine

(Vector Laboratories). The sections were counterstained with Mayer’s hematoxylin. Quantification of CoQ9 was performed as described.35 Plasma with internal standard CoQ11 was injected into an automated high-performance liquid chromatographic system equipped with a coulometer detector. selleck inhibitor Quantification of oxCoQ9 was obtained using ChromQuest software (Fisher Scientific, Pittsburgh, PA). After injection, the extract was mixed with 1,4-benzoquinone, incubated, and then injected into the high-performance liquid chromatographic system for measuring total CoQ9. Concentration of reduced coenzyme Q9 was achieved by subtracting oxCoQ9 from total CoQ9. Statistical comparison between groups and treatments was performed using one-way analysis of variance (ANOVA) and post hoc Tukey’s test. Student t tests were used when comparing two groups. A P value of <0.05 was considered statistically significant.

3). In contrast, the FIB-γ blot of livers undergoing hepatocyte apoptosis showed two major bands (100 kDa and 250 kDa) that are present only in the total liver homogenate and are markedly enriched in the pellet fraction but not in the soluble selleck chemical TX-100 or high salt fractions (Fig. 3). Taken together, these findings indicate that FIB-γ dimerizes

and becomes insoluble upon FasL-mediated liver injury. The above findings led us to hypothesize that FIB-γ shifts its location from plasma to the liver upon apoptotic injury. We tested this hypothesis by comparing serum, plasma, and liver FIB-γ levels before and after exposure to FasL. The FIB-γ 100 kDa dimer was detected in FasL-treated mouse serum but not in plasma, whereas this dimer and other high molecular weight (HMW) products were readily observed in the liver lysates (Fig. 4A). A separate analysis comparing the FIB-γ dimer and higher complexes in the clot from whole blood versus intact liver (boxed panels in Fig. 4B) shows a clear and marked shift from the clot to the liver. Therefore, the FIB-γ dimer and its HMW complexes accumulate

in the liver after FasL-mediated liver injury, which is consistent find more with intrahepatic IC. The intrahepatic IC is also supported by the increased levels of plasminogen activator inhibitor-1 in plasma and liver upon FasL-mediated liver injury, with concurrent increase in tissue factor levels in plasma (Supporting Fig. 1). The extensive intravascular coagulation within liver parenchyma after FasL-induced hepatocyte

apoptosis raised the hypothesis that anticoagulation using heparin may provide a protective effect. For this, we first defined a period whereby heparin is administered and maintains its anticoagulant effect prior to injecting FasL. Using a dose range of 10-100 U per mouse, we found that 20 U per mouse provided anticoagulation that is similar to the higher tested doses (based on elevation of plasma fibrinogen levels without leading to significant hematoma formation, not shown). Based on this dosing regimen, heparin was administered subcutaneously followed 4 hours later by FasL administration. The extent of injury in these mice was then compared with mice given FasL alone (Fig. 5). Histological analysis of the livers showed a dramatic decrease in the extent see more of hemorrhage in mice that were given heparin (Fig. 5A, Supporting Fig. 2). Heparin pretreatment also resulted in a dramatic decrease in TUNEL staining (Fig. 5A). These findings were supported by significantly reduced serum ALT levels (4.8-fold) and lower liver apoptotic cell number in the heparin-pretreated mice (Fig. 5B,C). In addition, biochemical analysis showed that the activation of caspases 3 and 7 and formation of the K18 apoptotic fragment were markedly blunted in mice that received heparin (Fig. 5D). These biochemical changes also paralleled the detection of the FIB-γ dimer (Fig. 5D).