BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk.

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCß-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Cost- Effectiveness of Avatrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease.

BACKGROUND AND AIM: Thrombocytopenia is common in people with chronic liver disease, who frequently undergo invasive procedures. To minimize the risk of bleeding, prophylactic platelet transfusions have traditionally been used but carry many risks. The aim of this study was to evaluate the cost-effectiveness of avatrombopag compared with platelet transfusion and lusutrombopag as a treatment for thrombocytopenia in adult patients with chronic liver disease scheduled to undergo a medical procedure. METHODS: A decision-tree model was developed from a US payer perspective to capture acute events observed in phase 3 global randomized controlled clinical trials and, to support exploratory analyses, potential longer-term complications resulting from a major bleed or thromboembolic event. Treatment costs were taken from publicly available data sources. The interventions were evaluated in the overall trial populations and in subpopulations with higher and lower baseline platelet counts. Results were presented as incremental cost per platelet transfusion avoided. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In the overall population, avatrombopag reduced the need for platelet transfusions and produced cost-savings compared with platelet transfusion (80% fewer prophylactic platelet transfusions, $4250 lower costs) and lusutrombopag (42% fewer prophylactic platelet transfusions, $5819 lower costs). Similar results were seen in both the higher and lower platelet count subpopulations. The one-way and probabilistic sensitivity analyses found that the use of avatrombopag is cost-saving with the incremental cost-effectiveness ratio in quadrant IV (decreased costs, prophylactic platelet transfusions avoided). CONCLUSION: The use of avatrombopag is expected to be cost-saving while reducing the need for prophylactic platelet transfusions compared with platelet transfusion and lusutrombopag.

Distinct roles of NMB and GRP in itch transmission.

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.

Estimating the Incidence and Prevalence of Chronic Hepatitis C Infection in Taiwan Using Back Projection.

OBJECTIVE: Hepatitis C virus (HCV) infection is the leading cause of liver disease, and Taiwan has among the highest prevalence of HCV infection in the general population in Northeast Asia, estimated at between 2% and 4%. The aim of this study was to estimate the number of patients living with chronic HCV infection in Taiwan and quantify the expected numbers in each of the five Metavir fibrosis stages. METHODS: We applied a back-projection approach, using observed hepatocellular carcinoma incidence between 1979 and 2008 and a smoothed Expectation-Maximization algorithm to maximize a Poisson likelihood to estimate the previous incidence of HCV infection. The algorithm was coded in Excel and combined with the MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis model (a hepatitis C natural history markov model) to predict the past and future numbers in each Metavir fibrosis stage. RESULTS: Incident cases were predicted to have peaked in 1972 at 56,634 annually, with the prevalence peaking in 1986 at 763,737 infections and falling to 578,203 infections in 2012. It was estimated that in 2012, 127,795 (23.0%), 105,545 (19.0%), 81,211 (14.6%), 123,939 (22.3%), and 116,823 (21.1%) subjects were in fibrosis stages F0, F1, F2, F3, and F4, respectively. DISCUSSION: Our study provides HCV infection prevalence estimates, stratified by Metavir fibrosis stage, in Taiwan for 2012. This has potential implications for budget planning, particularly with the availability of emerging therapies because fibrosis stage is predictive of both rapid and sustained virological response; therefore, planning expected treatment response in a given population could be enhanced with this additional information.

SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine.

The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human SIRT6 efficiently removes long-chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of SIRT6 reveals a large hydrophobic pocket that can accommodate long-chain fatty acyl groups. We demonstrate further that SIRT6 promotes the secretion of tumour necrosis factor-α (TNF-α) by removing the fatty acyl modification on K19 and K20 of TNF-α. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data indicate that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of SIRT6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of a protein post-translational modification that has been little studied until now.

The impact of timing and prioritization on the cost-effectiveness of birth cohort testing and treatment for hepatitis C virus in the United States.

UNLABELLED: Recent United States guidelines recommend one-time birth cohort testing for hepatitis C infection in persons born between 1945 and 1965; this represents a major public health policy undertaking. The purpose of this study was to assess the role of treatment timing and prioritization on predicted cost-effectiveness. The MONARCH hepatitis C lifetime simulation model was used in conjunction with a testing and treatment decision tree to estimate the cost-effectiveness of birth cohort versus risk-based testing incorporating information on age, fibrosis stage and treatment timing. The study used a 1945-1965 birth cohort and included disease progression, testing and treatment-related parameters. Scenario analysis was used to evaluate the impact of hepatitis C virus (HCV) prevalence, treatment eligibility, age, fibrosis stage and timing of treatment initiation on total costs, quality-adjusted life years (QALYs), HCV-related complications and cost-effectiveness. The cost-effectiveness of birth cohort versus risk-based testing was $28,602. Assuming 91% of the population is tested, at least 278,000 people need to be treated for birth cohort testing to maintain cost-effectiveness. Prioritizing treatment toward those with more advanced fibrosis is associated with a decrease in total cost of $7.5 billion and 59,035 fewer HCV-related complications. Total QALYs and complications avoided are maximized when treatment initiation occurs as soon as possible after testing. CONCLUSION: This study confirms that birth cohort testing is, on average, cost-effective. However, this remains true only when enough tested and HCV-positive subjects are treated to generate sufficient cost offsets and QALY gains. Given the practical and financial challenges associated with implementing birth cohort testing, the greatest return on investment is obtained when eligible patients are treated immediately and those with more advanced disease are prioritized.

Assessing the cost utility of response-guided therapy in patients with chronic hepatitis C genotype 1 in the UK using the MONARCH model.

BACKGROUND: European guidelines advocate the measurement of on-treatment hepatitis C virus (HCV) RNA in order to determine optimal therapy duration (response-guided therapy [RGT]) in patients with rapid virological response (RVR) or delayed virological response (DVR). Treatment response is highly dependent upon the extent of liver fibrosis yet there is little evidence quantifying the cost effectiveness of RGT particularly conditional upon fibrosis stage. OBJECTIVE: This study describes an economic model designed to assess the costs and benefits of RGT compared with standard duration of therapy (SDT) in hepatitis C virus genotype 1 patients. METHODS: A Markov cohort simulation model with lifetime perspective was developed to undertake a cost utility analysis of RGT in the UK. Patients entered the model at Metavir disease stages F0-F4, and progressed through these stages via age and duration of HCV infection-dependent transition probabilities. Treated patients were partitioned according to virological response and shortened or extended duration of therapy was applied following European guidelines. RESULTS: For all patients, SDT and RGT was associated with an increase of 2.14 and 2.20 QALYs and £2,374 and £2,270 costs, respectively, compared with no treatment. Overall, RGT was a dominant scenario being associated with a lower risk of complications, increased QALYs (0.08) and cost saving (£101). RGT across fibrosis stages was either highly cost effective or dominant; in all cases RGT was associated with an increase in QALYs, driven by a reduction in complications in DVR subjects and reduced exposure to treatment disutility in RVR subjects; costs were lower in F1 and F2 fibrosis stages. At a willingness-to-pay threshold of £20,000 per QALY, overall RGT across fibrosis stages F2-F4 were associated with the highest probability of being cost effective. At this threshold, the probability of reduced/extended therapy in RVR/DVR patients being cost effective is 0.35 and 0.88, respectively. CONCLUSIONS: This analysis suggests that the treatment of HCV genotype 1 patients in fibrosis stage F2 has the greatest potential for maximizing health benefit and cost saving within an RGT protocol. Predicting those patients most likely to respond to treatments is important from both a clinical and cost perspective and the tailoring of treatment duration with the current standard of care is likely to remain a priority for payers with budgetary constraints.

Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites.

Advanced cirrhosis is often complicated by a multi organ failure syndrome which involves many different organs besides the liver. The high morbidity and mortality secondary to this clinical setting is often related to renal dysfunction, either alone or, more frequently, in combination with other organ dysfunction. A clear definition of renal dysfunction, an accurate differential diagnostic process of its different phenotypes as well as of full understanding of its pathophysiological mechanisms are crucial to the development of strategies for the management of this complication. This article is based either on the more recent knowledge on renal dysfunction in advanced cirrhosis or current opinions among the members of the International Club of Ascites (ICA) on the management of this complication, obtained through a survey and discussed during the EASL-ICA Joint Meeting in Berlin in March 2011. It reviews critically our current knowledge and it outlines future perspectives, on the management of renal dysfunction in patients with cirrhosis.

Isoform-specific alanine aminotransferase measurement can distinguish hepatic from extrahepatic injury in humans.

Serum alanine aminotransferase (ALT) is used as a clinical marker to detect hepatic damage and hepatoxicity. Two isoforms of ALT have been identified, ALT1 and ALT2, which have identical enzymatic capacities and are detected simultaneously in human serum/plasma using classical clinical chemical assays. Differences exist in the expression patterns of the ALT1 and ALT2 proteins in different organs which suggest that changes in the proportion of ALT1 and ALT2 in plasma may arise and reflect damage to different human organs. However, this has not been previously studied due to the lack of a selective methodology that can quantify both ALT1 and ALT2 isoforms in the total ALT activity normally measured in clinical samples. To the best of our knowledge, our current study reveals for the first time, that under 3 different conditions of liver damage (non-alcoholic fatty liver disease, hepatitis C and during liver surgery) the leakage of ALT1 activity into plasma greatly exceeds that of ALT2, and that the measurement of ALT1 during liver damage is equal to the measurement of total ALT activity. By contrast, during skeletal muscle injury, induced in volunteers by physical exertion, the leakage of ALT2 exceeds that of ALT1 and the proportion of circulating ALT isoforms changes accordingly. The ALT isoform changes occurring in plasma reflect previously demonstrated relative contents of ALT1 and ALT2 activities in human liver and skeletal muscle. These data suggest that assessing the percentage contribution of ALT1 and ALT2 activities to total ALT activity in plasma may distinguish hepatic from extrahepatic injury using the same standard analytical platform.

Structural frameworks and key model parameters in cost-effectiveness analyses for current and future treatments of chronic hepatitis C.

OBJECTIVES: Published economic evaluations have reported available treatments for chronic hepatitis C to be cost-effective as part of the current approach to disease management, but as standards of care evolve, their approach to modeling should be reconsidered. This study aimed to review structural frameworks and key model parameters as reported in current economic evaluations for treatments for chronic hepatitis C, and model the impact of variability across parameters on results. METHODS: A systematic review of studies published from 2000 to 2011 was performed. Studies were retrieved from five electronic databases using relevant search strategies. Model structures, disease progression rates, utilities, and costs were extracted from included studies, and were qualitatively reviewed and incorporated into a cost-utility model. RESULTS: Thirty-four studies were appropriate for data extraction. A common pathway of six disease states was identified. In some studies the early disease stages and/or the decompensated cirrhosis state were further subdivided. Large variability in values used for disease progression rates, utilities, and costs were identified. When incorporated into a model, incremental cost-effectiveness ratios (ICERs) varied: in the least favorable scenario, peginterferon plus ribavirin was dominated by interferon plus ribavirin; and in the most favorable scenario, peginterferon plus ribavirin dominated interferon plus ribavirin ($8,544 per quality-adjusted life year [QALY]; costs are given in 2008 US dollar amounts). Using mean values the ICER was $15,198 per QALY. CONCLUSIONS: Current models use a simplistic structure resulting from the lack of available data reflecting patient heterogeneity. Key model parameters are currently based on a small number of studies and the variability across these values can affect the interpretation of results.

Model for end-stage liver disease (MELD) and allocation of donor livers.

BACKGROUND & AIMS: A consensus has been reached that liver donor allocation should be based primarily on liver disease severity and that waiting time should not be a major determining factor. Our aim was to assess the capability of the Model for End-Stage Liver Disease (MELD) score to correctly rank potential liver recipients according to their severity of liver disease and mortality risk on the OPTN liver waiting list. METHODS: The MELD model predicts liver disease severity based on serum creatinine, serum total bilirubin, and INR and has been shown to be useful in predicting mortality in patients with compensated and decompensated cirrhosis. In this study, we prospectively applied the MELD score to estimate 3-month mortality to 3437 adult liver transplant candidates with chronic liver disease who were added to the OPTN waiting list at 2A or 2B status between November, 1999, and December, 2001. RESULTS: In this study cohort with chronic liver disease, 412 (12%) died during the 3-month follow-up period. Waiting list mortality increased directly in proportion to the listing MELD score. Patients having a MELD score <9 experienced a 1.9% mortality, whereas patients having a MELD score > or =40 had a mortality rate of 71.3%. Using the c-statistic with 3-month mortality as the end point, the area under the receiver operating characteristic (ROC) curve for the MELD score was 0.83 compared with 0.76 for the Child-Turcotte-Pugh (CTP) score (P < 0.001). CONCLUSIONS: These data suggest that the MELD score is able to accurately predict 3-month mortality among patients with chronic liver disease on the liver waiting list and can be applied for allocation of donor livers.