In the present article the effects of drug binding (both specific and nonspecific) in the porous arterial wall following stent-based drug delivery from drug-eluting stents (DESs) are investigated. A three-phase (free, extracellular matrix-bound, and specific receptor-bound) second-order nonlinear saturable reversible binding model is considered in order to describe the binding process with the constituents of the porous arterial wall. Although, there are currently some precise forms of a drug binding model in the arterial tissue in the literature, analyzed by various authors. The specific interest in this present context is in assessing to what extent modelling of specific and nonspecific binding within a single-layered homogeneous porous arterial wall is possible. A novel axi-symmetric model of drug delivery from three stent struts has been developed and is presented.

The governing equations of motion together with the physiologically realistic boundary conditions are tackled numerically by an explicit finite-difference scheme in staggered grids.

Results include the influence of the significant model parameters, such as Peclet numbers (PeT, Pe1 and Pe2), Damköhler numbers (Da1 and Da2) and time-dependent release kinetics as well as constant release kinetics. Consistency of the proposed approach is shown graphically.

As the porosity (εw) increases, the effective as well as the true diffusivity increases, which eventually leads to expedition of the diffusion process. In a porous media, diffusion takes place in confined tortuous pores and its progression is impeded as the tortuosity increases. The present simulation also demonstrates a decrease in the mean concentration of free as well as extracellular matrix-bound and SR-bound drug with increasing tortuosity. The present observation may be justified in the sense that as the tortuosity increases so too does the effective distance over which diffusion has to take place (i.e. the progression of diffusion is impeded, which eventually lowers the mean concentration of all drug forms).

Gut microbiota changes play a key role in the pathogenesis of hepatic encephalopathy (HE). Fecal microbiota transplantation (FMT) is an efficient way to manipulate the gut microbiota. This review collects the experimental and clinical evidence that supports the use of FMT in the treatment of HE. Animal experiments showed that the blood ammonia level, mortality and cognitive impairment were decreased when animals with HE were transplanted with the selected gut microbiota or the fecal material from human donor. Successful clinical application of FMT for treating HE was first reported in 2016. A subsequent randomized clinical trial demonstrated further that FMT from a “rationally selected donor” reduced hospitalizations and improved cognition and dysbiosis in patients with recurrent HE. Possible underlying mechanisms of FMT treating HE include restoration of the impaired gut-liver-brain axis, as well as reduction of ammonia production, systemic inflammation and blood-brain barrier permeability.

Background and Aims: Hepatic encephalopathy is a liver disease complication with significant mortality and costs. The aim of this study was to evaluate the relative performance of facilities based on their teaching status and transplant capability by correlating their connections to mortality, cost, and length of stay from 2007 to 2014.

Methods: The Nationwide Inpatient Sample database was utilized to collect information on (USA) American patients admitted with a primary diagnosis of hepatic encephalopathy from 2007–2014. Hospitals were placed into one of four categories using their teaching and transplant status. Using regression analysis, mortality, length of stay and cost adjusted rate ratios were calculated.

Results: The study revealed that teaching transplant centers had a mortality risk ratio of 0.783 (95% confidence interval (CI): 0.750–0.819, p < 0.001). Blacks had the highest mortality risk ratio, of 1.273 (95%CI: 1.217–1.331, p < 0.001). Furthermore, teaching transplant hospitals had a cost rate ratio of 1.226 (95%CI: 1.214–1.238, p < 0.001) and a length of stay rate ratio of 1.104 (95%CI: 1.093–1.115, p < 0.001).

Conclusions: It appears that admission to transplant facilities for hepatic encephalopathy is associated with reduced mortality but increased costs and longer stay independent of transplantation. Moreover, factors impacting black mortality should also be examined more closely.

Procalcitonin (PCT) is a widely used biomarker for the diagnosis of bacterial infections. It is produced by various organs and the liver is considered to be the most important site of production. Severe liver dysfunction has been shown to influence PCT levels. Patients with no sources of infection who have liver disease are observed to have increased serum levels of PCT, thereby reducing the diagnostic utility and value within this particular patient subset. Here, we have summarized the relationship between PCT and liver disease, including liver cirrhosis, liver failure, and liver transplantation.

Background and Aims: Intoxications by aliphatic halogenated hydrocarbons (AHH), used as effective solvents, are rare and may cause life-threatening liver injury. Patients with acute intoxications by AHH received an innovative treatment.

Methods: Analyzed were data of 60 patients intoxicated by AHH, such as dichloromethane (n = 3), chloroform (n = 2), carbon tetrachloride (n = 12), 1,2-dichloroethane (n = 18), 1,1,2-trichloroethane (n = 2), trichloroethylene (n = 2), tetrachloroethylene (n = 13) or mixed AHH chemicals (n = 8), who received a new treatment consisting of CO2-induced hyperventilation to accelerate toxin removal via the lungs.

Results: Added to the inspiration air at a flow rate of 2–3 Liter min−1, CO2 increased the respiratory volume up to 25–30 Liter min−1, ensuring forced AHH exhalation. This CO2-induced hyperventilation therapy was commonly well tolerated by the 60 patients and lasted for 106.0±10.5 hours. In most cases, initially increased liver test results of aminotransferases normalized quickly under the therapy, and liver histology obtained at completion of the therapy revealed, in the majority of patients, normal findings or fatty changes, and rarely severe single cell necrosis but no confluent liver cell necrosis. Despite therapy, clinical outcome was unfavorable for 4/60 patients (6.7%) of the study cohort, due to single or combined risk factors. These included late initiation of the CO2-induced hyperventilation therapy, intentional intoxication, uptake of high amounts of AHH, concomitant ingestion of overdosed drugs, consumption of high amounts of alcohol, and history of alcohol abuse.

Conclusions: For intoxications by AHH, effective therapy approaches including forced hyperventilation to increase toxin removal via the lungs are available and require prompt initiation.

Biliary atresia (BA) is a childhood disease which manifests with abnormal narrowing, blockage or complete absence of bile ducts within the liver. Many possible etiologies have been reported for the development of BA, including congenital, perinatal and acquired conditions. Since the 1970’s, there has been increasing evidence linking BA development to viral perinatal infections. The viral vectors most commonly implicated include members of the herpesviridae family (cytomegalovirus and Epstein-Barr virus) as well as those of the reoviridae family (reovirus and rotavirus). While extensive work has been done on a murine model of disease, the current review focuses primarily on evidence from human studies of viral vectors in children afflicted with BA.

Background and Aims: Studies have indicated that serum von Willebrand factor (vWF) has a positive correlation with hepatic venous pressure gradient. However, information on the value of vWF in the diagnosis of liver cirrhosis with portal hypertension has been lacking. The purpose of this meta-analysis was to assess the value of vWF in the diagnosis of liver cirrhosis with portal hypertension.

Methods: Studies that analyzed the sensitivity, specificity, diagnostic odds ratio combined with likelihood ratios and test for heterogeneity of vWF in the diagnosis of liver cirrhosis with portal hypertension were found in the Cochrane Library, Ovid, VOS-SCI, CNKI, PubMed, Medline, EMBASE, CMB and Wanfang databases. In the end, the data was used to draw the summary receiver operating characteristic curve and to calculate the area under the curve.

Results: Four studies involving 662 patients were analyzed. The results showed that serum vWF in liver cirrhosis with portal hypertension were significantly higher than in those without portal hypertension. Sensitivity combined was 0.823 (95% CI: 0.788, 0.855). Specificity combined was 0.782 (95% CI: 0.708, 0.845). +LR combined was 3.777 (95% CI: 2.794, 5.107). -LR combined was 0.221 (95% CI: 0.180, 0.272). Diagnostic odds ratio combined was 18.347 (95% CI: 11.725, 28.708). The area under the curve was 0.8896.

Conclusions: Serum vWF can be used as an effective and feasible method for noninvasive diagnosis of liver cirrhosis with portal hypertension. However, further studies are still needed to evaluate the severity of liver cirrhosis with portal hypertension.

Background and Aims: The serine proteinase inhibitor alpha-1 anti-trypsin (AAT) protects the body against protease activity. Several functions of AAT beyond those attributed to its anti-protease activity have been described, among them immunomodulatory and anti-inflammatory properties. The present study aimed to determine the efficacy of AAT for the treatment of immune-mediated liver injury using the models of concanavalin A-induced immune-mediated hepatitis and acetaminophen -induced liver damage.

Methods: AAT was administered to mice subjected to concanavalin A-induced immune-mediated hepatitis or 2 h after acetaminophen-induced liver damage. Mice were followed for changes in serum levels of liver enzymes, liver histology, and for interferon gamma serum levels.

Results: Treatment with AAT alleviated concanavalin A-induced immune-mediated liver damage, as demonstrated by a reduction in the serum levels of liver enzymes and interferon gamma, and an improved lymphocyte infiltration into the liver on liver biopsies. Moreover, treatment with AAT was associated with alleviation of the acetaminophen-induced liver injury.

Conclusions: AAT exerts an hepatoprotective effect on immune-mediated and drug-induced liver damage. The data support its potential use in patients with immune-associated liver disorders.

Background and Aims: Although hypovitaminosis D is common among patients with chronic liver disease (CLD), the data are inconsistent on its prevalence and its relationship with CLD. This study aimed to estimate the prevalence of hypovitaminosis D among patients with CLD and to determine the relationship between hypovitaminosis D and severity of liver dysfunction, and calcium (Ca), phosphate (PO4) and parathyroid hormone (PTH) levels in CLD.

Methods: The study included 236 CLD patients attending the Department of Hepatology, Rajiv Gandhi Government General Hospital (Chennai, India). Serum levels of 25-hydroxyvitamin D (25(OH)D), PTH, Ca, and PO4 were estimated. Severity of liver dysfunction was graded using the Child–Turcotte–Pugh (CTP) score.

Results: The first report from our population showed that 162 of 236 (68.6%) CLD patients had hypovitaminosis D (25(OH)D levels of <30 ng/mL), with higher frequency (124/162) 76.5% among CTP B, C patients. Significant negative correlation (r = −0.288, p = 0.0001) between 25(OH)D and CTP scores was noted in hypovitaminosis D conditions. Level of 25(OH)D was correlated negatively with PTH (r = −0.537, p = 0.0001), positively with Ca (r = 0.657, p = 0.0001), and positively with PO4 (r = 0.477, p = 0.0001) in sufficient vitamin D conditions.

Conclusions: Hypovitaminosis D is associated with higher CTP scores and is strongly associated with dysregulation of the Ca-PTH-vitamin D axis in CLD. Timely measurement of vitamin D levels is essential, along with levels of PTH, Ca and PO4, to manage CLD patients.

Bile acids (BAs) are the major metabolic product of cholesterol, having detergent-like activities and being responsible for absorption of lipid and lipid-soluble vitamins. In addition, it has been increasingly recognized that BAs are important signaling molecules, regulating energy metabolism and immunity. Under physiological circumstances, synthesis and transport of BAs are precisely regulated to maintain bile acid homeostasis. Disruption of bile acid homeostasis results in pathological cholestasis and metabolic liver diseases. During the last decades, BAs have been gradually recognized as an important therapeutic target for novel treatment in chronic liver diseases. This review will provide an update on the current understanding of synthesis, transport and regulation of BAs, with a focus on the therapeutic roles of bile acid signaling in chronic liver diseases.

Maternal mortality remains a global health problem. Preeclampsia and eclampsia, major hypertensive disorders in pregnancy, remain the fourth leading cause of maternal mortality. The role of aspirin to prevent preeclampsia has been explored in the last 3 decades. This article summarizes the various studies done so far on the role of aspirin in preeclampsia and seeks to develop a hypothesis regarding the indication, dose and efficacy of aspirin therapy in the prevention of preeclampsia. Aspirin, when administered at 12–20 weeks of gestation at a dose of 75–150 mg seems to have a role in primary and secondary prevention of preeclampsia in high-risk pregnant women. The existing screening algorithms for preeclampsia have a high false positive rate. Therefore, a need for further research to develop a better screening algorithm for detection of women at a high risk of preeclampsia is warranted. The results, from the recent Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) study, reported better prevention of preeclampsia with a 150 mg dose of aspirin. Hence, more data from multicentric randomized controlled trials are required to establish the safety and higher effect size of 120–150 mg dose aspirin compared to the 75–100 mg dose of aspirin for prevention of preterm preeclampsia.

Obstructive jaundice in the setting of a hilar mass raises strong suspicion of a cholangiocarcinoma, with diagnosis usually made on imaging. Jaundice, when present in patients with hepatocellular carcinoma, is mostly related to underlying liver disease (i.e. cirrhosis) and only rarely to diffuse tumor infiltration of liver parenchyma or hilar invasion. We report here the good outcome of a 67 year-old patient who presented with obstructive jaundice, underwent surgery and was given a diagnosis of hepatocellular carcinoma, which was made only at histopathological examination of resected specimen.

Specific and rapid detection of snake venom type is a complex practice, even with the contemporary medical technology. Generally, in cases for which the species are not identified, the nonspecific polymeric antivenom is injected into the patient. Thus, the effectiveness of treatment is limited, as it acts arbitrarily on the target. Since most snakes are nonpoisonous and treatment is applied with a cautionary approach, the patient can experience severe side effects of a nonspecific agent and in some cases mortality. Therefore, there is an immediate need to develop a suitable medical methodology to avoid this arbitrary practice. The proposed hypothesis may be the best practice for rapid and specific determination of snake venom type by biosensor intervention.

During sperm maturation, chromatin undergoes an extensive compaction through the progressive replacement of histones with basic, positively-charged proteins called protamines. Interestingly, in human and other vertebrates, 5–15% of the paternal genome retains a somatic-like structure. It has been suggested that preserved nucleosomes have a role in promoting transcription after fertilization, however their localization and function is still a matter of debate. The aim of the present work was to understand if the localization of histones in human sperm DNA is affected by genome composition, a feature linked to several biological functions. In order to do that, we mapped histone-enriched sequences along isochores, which are large chromosomal territories characterized by fairly homogeneous guanine and cytosine (GC) composition.

We retrieved publicly available human sequences found to be histone-enriched in sperm chromatin and localized them along isochores by using their respective coordinates.

We found that the majority of genes and sequences associated with mononucleosomes, the activating chromatin mark H3K4me3 and the repressive mark H3K27me3 reside in the GC-poor isochores. Genes harboring the activating mark H3K4me2, instead, are preferentially located in the GC-rich isochores.

For genes carrying histones with specific marks, we speculate that developmental and tissue-specific genes (carrying the H3K27me3 mark) might take advantage by residing in GC-poor isochores because in these regions they can be shut off immediately after the end of their transcription more easily than in GC-rich isochores. On the contrary, housekeeping genes (marked with H3K4me2) would not need this kind of regulation and reside in GC-rich isochores. For other genes and sequences, further analyses are required in order to clarify the role of GC composition in histone retention in sperm chromatin. In conclusion, although the complete scenario of sperm chromatin has not been elucidated yet, correlations seem to exist between chromatin modification patterns, isochore structure and gene expression timing in embryo development.

Ribavirin, once a staple of hepatitis C treatment, has significant drawbacks, including treatment-limiting side effects, the requirement for intensive laboratory monitoring, the need for frequent dose adjustments, and teratogenicity. These factors make it difficult to escalate ribavirin-based HCV treatment to most infected patients globally. Most studies have shown comparable response rates between ribavirin-inclusive and ribavirin-sparing regimens in uncomplicated patient populations. However, ribavirin is still used in the management of patients who have failed previous therapy as well as those with decompensated liver disease. In this review, we explore the evidence supporting the use of ribavirin in the current climate of hepatitis C treatment with oral combination direct-acting antiviral agents.

Metastatic renal cell cancer is typically resistant to chemotherapy but does respond to vascular endothelial growth factor receptor signal transduction inhibition and to a variety of immunotherapies, including interleukin (IL)-2 and monoclonal antibodies that inhibit immune checkpoints. Enhanced immune recognition of tumor antigens may improve clinical outcomes. The objective of this study was to investigate the effects of a patient-specific approach utilizing autologous dendritic cell vaccines and self-renewing autologous tumor cells in patients with metastatic renal cell carcinoma.

Short-term cell lines were established from resected renal cell cancer specimens. Autologous dendritic cells were derived from peripheral blood mononuclear cells cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Antigen loading was accomplished by incubating irradiated tumor cells with dendritic cells. The vaccine was admixed with GM-CSF and injected subcutaneously weekly for 3 weeks, then monthly for 5 months.

Short-term cell lines were established for 28 patients. Dendritic cells were produced for 11 patients. Nine patients were referred for treatment. The nine patients received 58 injections, and 6 received all 8 planned doses. Treatments were well-tolerated, other than mild to moderate injection site reactions. One patient experienced an anaphylactoid reaction attributed to microaggregates in GM-CSF. Three patients had conversion from negative to positive for a delayed-type hypersensitivity test to intradermal injection of one million autologous irradiated tumor cells. Two of seven patients had delayed complete regression of measurable oligometastatic disease. Three patients were still alive and disease-free after 5 years.

This patient-specific vaccine approach is feasible, well-tolerated, and associated with encouraging long-term survival in some patients. Larger trials of dendritic cells with autologous tumor antigens derived from self-renewing tumor cells, rather than bulk tumor, may be warranted.

Autophagy is a physiologic mechanism, which utilizes the self-digestion of cell organelles to promote cellular homeostasis, such as in the setting of dysfunctional cellular components, cellular stress or energy-deprived states. In vitro studies have pointed toward the key role of autophagy in colorectal cancer. However, in vivo studies from human colorectal cancer tissues are lacking.

We collected tissue samples from six patients with colon cancer who received curative surgery at Baylor College of Medicine. We also obtained normal colonic mucosa biopsy from five unrelated polyp-free individuals who were matched to cases individually by age, sex, ethnicity, and colon segment. Total RNA was successfully extracted from fresh frozen tissue biopsies of five tumor tissues and five unrelated normal tissues. We tested the expression levels of 84 genes in a predefined autophagy pathway using the RT2 Profiler PCR array. We compared differences using Student’s t-test. The false-discovery rate was used for multiple testing adjustment. We also used the TCGA dataset to validate our findings.

We observed significant differential expression between colon cancer tissue and normal colon mucosa for 29 genes in the autophagy pathway (p < 0.05). After multiple testing adjustment, the expression of 17 genes was significantly down-regulated, with fold-change greater than 2 in colon cancer; these included ATG4A, ATG4C, ATG4D, and CTSS (q < 0.10). The down-regulation was observed in both early and late stage colon cancer. We observed the same down-regulation of multiple autophagy-related genes using the TCGA data. The ATG9B gene was the only statistically non-significantly up-regulated gene after multiple testing adjustment.

This pilot study showed the down-regulation of multiple autophagy pathway genes in human colon cancer, corroborating the increasing clinical relevance of autophagy in human colorectal carcinogenesis. This preliminary finding should be validated in larger studies.

Background and Aims: Hepatitis C virus (HCV) infection results in hepatocytic injury with elevation of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It remains to be determined if direct-acting antiviral treatment can terminate hepatocytic injury following virologic response. To this end, we evaluated the pattern and predicting factors of ALT and AST normalization during and after direct-acting antiviral treatment with sustained virologic response at 12 weeks (SVR12).

Methods: Single-center retrospective study on 115 HCV-infected patients who achieved SVR12 was performed.

Results: At treatment week 2, 100% and 45.9% showed decline in HCV RNA to <700 IU/mL and undetectable levels, respectively, and this was associated with 85.5%, 83.9% and 77.4% ALT normalization, AST normalization and ALT and AST normalization. At end of treatment, 85.6% of patients with baseline elevation of both ALT and AST had normalization of both ALT and AST. At posttreatment weeks 12 and 24, 90.8% and 94.8% had normalization of both ALT and AST. HCV clearance also resulted in further decline of both ALT and AST in those with baseline <40 IU. Univariate analysis showed baseline Child-Pugh score of <6, model for end-stage liver disease score of <10, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2 were associated with sustained normalization of both ALT and AST at posttreatment week 12. On multivariate analysis, baseline model for end-stage liver disease score of <10 was significantly associated with normalization of both ALT and AST at posttreatment week 12, independent of baseline Child-Pugh score <6, HCV genotype 1, and HCV RNA of <500 IU/mL at treatment week 2.

Conclusions: During direct-acting antiviral therapy, 85.5% and 83.9% had normalization of both ALT and AST as early as in week 2, providing biochemical evidence of hepatocytic injury resolution. Sustained normalization of both ALT and AST was seen in 90.8% at posttreatment weeks 12, and was independently associated with baseline model for end-stage liver disease score of <10.