Background: The aim of this review was to identify the mechanisms by which serotonin
receptors involved at the central level are able to modulate the nociceptive response. Pain is a defense
mechanism ...of the body that entails physiological, anatomical, neurochemical, and psychological
changes, and is defined as an unpleasant sensory and emotional experience with potential
risk of tissue damage, comprising the leading cause of appointments with Physicians worldwide.
Treatment for this symptom has generated several neuropharmacological lines of research, due to
the different types of pain and the various drugs employed to treat this condition. Serotonin 5-
HydroxyTryptamine (5-HT) is a neurotransmitter with seven families (5-HT1–5-HT7) and approximately
15 receptor subtypes. Serotonin modulates neuronal activity; however, this neurotransmitter
is related with a number of physiological processes, such as cardiovascular function,
gastric motility, renal function, etc. On the other hand, several researches reported that serotonin
modulates nociceptive response through 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the Central
Nervous System (CNS).
Method: In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science
Citation Index for studies evaluating the effects of 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the
CNS on the modulation of different types of pain.
Conclusion We concluded that 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the CNS modulate the
pain, but this depends on the distribution of the receptors, dose of agonists or antagonists, administration
route, pain type and duration in order to inhibit, excite, or even maintain the nociceptive
response.
MicroRNAs (miRNAs) are well-known regulators of disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in alcoholic hepatitis (AH) and ...identifying miRNAs potentially involved in liver injury.
MiRNA profiling was performed in liver samples from patients with AH, alcohol liver disease, non-alcoholic steatohepatitis, HCV disease and normal liver tissue. Expression of miRNAs was assessed in liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-182's biological functions.
MiRNA expression profile in liver was highly altered in AH and distinctive from alcohol-induced cirrhotic livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced liver damage, bile acid accumulation and inflammatory response.
AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with disease severity and liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.
The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure that is not always readily accessible. We analyzed plasma biomarkers to estimate the presence ...of histological features of AH among patients with clinical suspicion of AH. Using enzyme‐linked immunosorbent assay, we tested M65 and M30 (circulating fragments of cytokeratin‐18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet, and endothelial‐derived MVs were quantified by way of flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46 of 83 (55%) patients showed histological features of AH. Age, bilirubin, INR, and creatinine (ABIC) score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV‐bound M65 and total and MV‐bound M30 and CCL20 than those without (P < 0.001 for all tests). Levels of TREM‐1 and of subpopulations of MVs were not different between groups. M65 and M30 both had an area under the receiver operating characteristics curve of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, whereas a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48 of 68 (71%) patients. ABIC score was B or C in 69% of patients. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Conclusion: Plasma levels of cytokeratin‐18 fragments are reliable noninvasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. (Hepatology 2017;66:555–563).
Background & Aims Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues ...to identify molecules associated with ASH progression and focused on the mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets. Methods C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 ( Fsp27Hep–/– mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor (GW9662) of peroxisome proliferator-activated receptor γ (PPARG). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanol-fed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed histologically and immunohistochemically and by transcriptome, immunoblotting, and real-time PCR analyses. Results Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including up-regulation of mouse Fsp27 (also called Cidec ) and human CIDEC. Fsp27Hep–/– mice and mice given injections of adenovirus- Fsp27 shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP-responsive element binding protein H (CREBH) prevented the increases in Fsp27α and FSP27β mRNAs, respectively, and reduced liver injury in this chronic-plus-binge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of mitochondrial reactive oxygen species and damage to hepatocytes in mice. Hepatic CIDEC mRNA expression was increased in patients with AH and correlated with the degree of hepatic steatosis and disease severity including mortality. Conclusions In mice, chronic-plus-binge ethanol feeding induces ASH that mimics some histological and molecular features observed in patients with AH. Hepatic expression of FSP27/CIDEC is highly up-regulated in mice following chronic-plus-binge ethanol feeding and in patients with AH; this up-regulation contributes to alcohol-induced liver damage.
Botulinum toxin type A (BoNT-A) is widely employed for cosmetic purposes and in the treatment of certain diseases such as strabismus, hemifacial spasm and focal dystonia among others. BoNT-A effect ...mainly acts at the muscular level by inhibiting the release of acetylcholine at presynaptic levels consequently blocking the action potential in the neuromuscular junction. Despite the great progress in approval and pharmaceutical usage, improvement in displacing BoNT-A to other pathologies has remained very limited. Patients under diagnosis of several types of cancer experience pain in a myriad of ways; it can be experienced as hyperalgesia or allodynia, and the severity of the pain depends, to some degree, on the place where the tumor is located. Pain relief in patients diagnosed with cancer is not always optimal, and as the disease progresses, transition to more aggressive drugs, like opioids is sometimes unavoidable. In recent years BoNT-A employment in cancer has been explored, as well as an antinociceptive drug; experiments in neuropathic, inflammatory and acute pain have been carried out in animal models and humans. Although its mechanism has not been fully known, evidence has shown that BoNT-A inhibits the secretion of pain mediators (substance P, Glutamate, and calcitonin gene related protein) from the nerve endings and dorsal root ganglion, impacting directly on the nociceptive transmission through the anterolateral and trigeminothalamic systems.
The study aimed to collect available literature regarding molecular, physiological and neurobiological evidence of BoNT-A in cancer patients suffering from acute, neuropathic and inflammatory pain in order to identify possible mechanisms of action in which the BoNT-A could impact positively in pain treatment.
BoNT-A could be an important neo-adjuvant and coadjuvant in the treatment of several types of cancer, to diminish pro-tumor activity and secondary pain.
Alcoholic hepatitis (AH) is a severe clinical condition that needs novel therapies. The identification of targets for therapy is hampered by the lack of animal models of advanced AH. The authors ...performed a translational study through a transcriptome analysis in patients with AH to identify new molecular targets.
Hepatic gene expression profiling was assessed by DNA microarray in patients with AH (n=15) and normal livers (n=7). Functional analysis was assessed by gene set enrichment analysis. Quantitative PCR was performed in patients with AH (n=40), hepatitis C (n=18), non-alcoholic steatohepatitis (n=20) and in mouse models of acute and chronic liver injury. Protein expression was assessed by immunohistochemistry and western blotting.
Gene expression analysis showed 207 genes >5-fold differentially expressed in patients with AH and revealed seven pathways differentially regulated including 'cytokine-cytokine receptor interaction'. Several tumour necrosis factor (TNF) superfamily receptors, but not ligands, were overexpressed in AH. Importantly, Fn14 was the only TNF superfamily receptor exclusively upregulated in AH compared with other liver diseases and correlated with both 90-day mortality and severity of portal hypertension. Fn14 protein expression was detected in areas of fibrogenesis and in a population of hepatocytes. Fn14 expression was increased in experimental models of liver injury and was detected in progenitor cells.
Translational research revealed that TNF superfamily receptors are overexpressed in AH. Fn14, the receptor for TNF-like weak inducer of apoptosis, is selectively upregulated in patients with AH. TNF superfamily receptors could represent a potential target for therapy.
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short‐term prognosis, whereas factors associated with long‐term survival are largely unknown. ...The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long‐term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long‐term follow‐up in patients with AH. One hundred forty‐two patients with biopsy‐proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow‐up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow‐up of 55 months. During follow‐up, complete abstinence was reported in 39% and was associated with better long‐term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End‐Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow‐up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%‐29%) rates of complete abstinence after an episode of AH. Conclusion: Complete abstinence after an episode of AH positively impacts long‐term survival. The combination of 2 variables easily obtained at admission might be useful to predict long‐term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842–1853)
Alcoholic hepatitis (AH) frequently progresses to multiple organ failure (MOF) and death. However, the driving factors are largely unknown. At admission, patients with AH often show criteria of ...systemic inflammatory response syndrome (SIRS) even in the absence of an infection. We hypothesize that the presence of SIRS may predispose to MOF and death. To test this hypothesis, we studied a cohort including 162 patients with biopsy‐proven AH. The presence of SIRS and infections was assessed in all patients, and multivariate analyses identified variables independently associated with MOF and 90‐day mortality. At admission, 32 (19.8%) patients were diagnosed with a bacterial infection, while 75 (46.3%) fulfilled SIRS criteria; 58 patients (35.8%) developed MOF during hospitalization. Short‐term mortality was significantly higher among patients who developed MOF (62.1% versus 3.8%, P < 0.001). The presence of SIRS was a major predictor of MOF (odds ratio = 2.69, P = 0.025) and strongly correlated with mortality. Importantly, the course of patients with SIRS with and without infection was similar in terms of MOF development and short‐term mortality. Finally, we sought to identify serum markers that differentiate SIRS with and without infection. We studied serum levels of high‐sensitivity C‐reactive protein, procalcitonin, and lipopolysaccharide at admission. All of them predicted mortality. Procalcitonin, but not high‐sensitivity C‐reactive protein, serum levels identified those patients with SIRS and infection. Lipopolysaccharide serum levels predicted MOF and the response to prednisolone. Conclusion: In the presence or absence of infections, SIRS is a major determinant of MOF and mortality in AH, and the mechanisms involved in the development of SIRS should be investigated; procalcitonin serum levels can help to identify patients with infection, and lipopolysaccharide levels may help to predict mortality and the response to steroids. (Hepatology 2015;62:762–772)
Importance Sampling and RESTART/Splitting are the two main groups of methods for rare event simulation. The second of these groups is increasingly used in a variety of fields, sometimes receiving ...different names, such as Subset Simulation or Forward Flux Sampling.
In both RESTART and Splitting a number of retrials (or paths) are made when the process reaches certain thresholds of a function of the system state, called the importance function. In RESTART all but one path are cut when they down-cross the threshold where they were generated and a new set of retrials is made if the trial that continues up-crosses that threshold. In Splitting, all the paths continue until the end-of-simulation condition is fulfilled but retrials are not performed if one of these trials up-crosses the threshold where the trial was generated. In the adaptive versions of Splitting or RESTART (introduced in this paper) the thresholds are not defined beforehand.
No simulation study has been made to compare both methods, while only one very limited comparative study was made for transient simulation between two truncation variants of Splitting and RESTART. In the truncation variant of Splitting all the simulation paths are cut if they drop several thresholds below the threshold at which they were generated. In the truncation version of RESTART, that we have called RESTART with prolonged retrials, all but one path are cut when they drop several thresholds and a new set of retrials is made if the trial that continues up-crosses the threshold where it was generated.
In this paper the comparative study is made for both transient and steady-state simulations. Both original methods and also their truncation versions with different depths of truncation are compared. The models used for the study include several Jackson and non-Jackson networks and also a general model of reliability with different types of components. The main conclusion of the study is that RESTART always behaves significantly better than Splitting. Another finding of this paper is that an additional gain (up to more than 50%) is achieved with RESTART with prolonged retrials of depths 1 or 2 in models where many thresholds can be set.
•The models used for the simulation study include several Jackson and non-Jackson networks and also a general model of reliability with different types of components.•Computational times with RESTART are much lower than with Splitting in all the models simulated.•A variant of RESTART with prolonged retrials increased the gain of RESTART up to more than 50%.•A new variant, adaptive RESTART, is described and compared theoretically with adaptive Splitting.
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