The sudden emergence in 2015 of neurologically complex infections attributed to the Zika virus (ZIKV) epidemic in Oceania and South America caught the medical and scientific world by surprise. The virus, which was detected often by serological tests, was known to circulate in Africa and in South/South-East Asian countries, causing mild febrile illness accompanied by nausea and aches, and often confused with dengue and chikungunya. How such an apparently benign virus could suddenly become so highly pathogenic–causing unprecedented levels of infections and an epidemic that affected fetuses in pregnant women to manifest microcephaly and other neurological disorders in newborns—is not yet understood, nor are there any drugs or vaccines to inhibit its progress. In this review, we recount the epidemiological aspects of the ZIKV spread, its clinical manifestations and diagnosis, and the genetics of the virus; we also narrate the efforts to understand the causes of the epidemic strains and discuss different designs of preventives and therapeutics.

Hepatitis E is an infectious inflammatory disease of the liver caused by the hepatitis E virus (HEV), a single-stranded RNA virus. Today, it is estimated that there are more than 20 million HEV infections every year, leading to 3.3 million symptomatic cases and more than 56,000 deaths. For a long time it was believed that HEV was a travel-associated disease, endemic in developing countries with poor hygienic standards and unsafe water supply. However, over the past years, publications have demonstrated that autochthonous HEV infections in industrialized countries are far more common than previously thought. Awareness for HEV amongst health care practitioners in industrialized countries is still limited. This relatively rare disease is of great importance, especially in immunocompromised patients where it can cause chronic liver disease. This article comprehensively reviews current literature to give an overview on clinically important topics. It will focus on epidemiological aspects, acute and chronic HEV infection as well as extra-hepatic manifestations, diagnostic approach and treatment options. Furthermore, the article is concluded with a brief outlook on perspectives and urgent problems to be addressed in the future.

Elevated liver enzymes are a common scenario encountered by physicians in clinical practice. For many physicians, however, evaluation of such a problem in patients presenting with no symptoms can be challenging. Evidence supporting a standardized approach to evaluation is lacking. Although alterations of liver enzymes could be a normal physiological phenomenon in certain cases, it may also reflect potential liver injury in others, necessitating its further assessment and management. In this article, we provide a guide to primary care clinicians to interpret abnormal elevation of liver enzymes in asymptomatic patients using a step-wise algorithm. Adopting a schematic approach that classifies enzyme alterations on the basis of pattern (hepatocellular, cholestatic and isolated hyperbilirubinemia), we review an approach to abnormal alteration of liver enzymes within each section, the most common causes of enzyme alteration, and suggest initial investigations.

Chronic hepatitis C virus (HCV) infection remains the leading indication for liver transplantation (LT) in the United States. While most patients with chronic HCV infection remain asymptomatic, up to one-third develop progressive liver disease resulting in cirrhosis. LT is often the only curative treatment once significant hepatic decompensation develops. However, antiviral therapy for HCV infection has advanced markedly in the past 5 years with the discovery and approval of direct-acting antiviral agents. These new regimens are well tolerated, of short duration and highly effective, unlike the traditional treatment with pegylated-interferon and ribavirin. As achieving sustained virological response becomes increasingly attainable for a majority of HCV-infected patients, concerns have been raised regarding the optimal timing of treatment for HCV infection in the setting of end-stage liver disease and during the peri-transplant period. On one hand, HCV treatment may improve hepatic function and negate the need for LT in some, which is crucial given the scarcity of donor organs and mortality on the waiting list in certain regions. On the other hand, HCV treatment may result in lowering the priority for LT without improving quality of life, thereby delaying potentially curative LT surgery. This review evaluates the evidence supporting the use of direct-acting antiviral agents in the period before and following LT.

Large-scale screening has revealed that human hematopoietic cancer cell lines are generally more sensitive to various classes of drugs than cell lines established from solid tumors. A detailed examination of data in the Cancer Therapeutics Response Portal (http://portals.broadinstitute.org/ctrp/ ) suggests that this enhanced sensitivity is due to lower basal levels of activation of TAZ-TEAD mechanotransduction pathways in hematopoietic versus non-hematopoietic cells. Translation inhibitors such as omacetaxine mepesuccinate (homoharringtonine) fall into this category of hematopoietic-selective compounds. Moreover, additional molecular determinants of sensitivity suggest that homoharringtonine might show therapeutic efficacy in certain patients with advanced hematologic malignancies despite activation of these pathways.

Background and Aims: Occult HCV infections (OCIs) include IgG antibody seronegative cryptogenic (COCIs), as well as seropositive secondary naïve (SNOCIs) and experienced (SEOCIs) cases. We used peripheral-blood-mononuclear-cell (PBMC)-PCR to evaluate COCIs and SNOCIs prevalence, serum HCV spontaneous disappearance (SCSD) in naïve cirrhotics and non-cirrhotics, intra-PBMC HCV-RNA strands in relation to cirrhosis density in naïve non-viremia cases, and HCV-RNA seroconversion after 1 year of solitary naïve intra-PBMC infection.

Methods: The anti-HCV IgG antibody-positive naïve-patients (n = 785) were classified into viremic (n = 673) and non-viremic [n = 112, including non-cirrhotics (n = 55) and cirrhotics (n = 57)], and 62 controls without evidence of HCV-infection. Controls and post-HCV non-viremia cases (n = 62+112 = 174) were submitted to hepatic Fibroscan-Elastography evaluation. All subjects (n = 847) were screened for intra-PBMC HCV-RNA sense and antisense strands by nested-PCR.

Results: Naïve-OCI cases (4.84%) that were diagnosed by PBMC-PCR significantly raised the total numbers of HCV-infection to 714 (p = 0.01). The percent positivity of SNOCIs (34.82%) was significantly higher than for asymptomatic-COCIs (3.125%, p = 0.0001). Comparing PBMC-PCR with single-step-reverse-transcription (SRT)-PCR for identification of SCSD in naïve IgG antibody-positive non-viremia patients (n = 112) revealed a decline in SCSD prevalence by PBMC-PCR (from 14.27% to 9.3%), regardless of presence of hepatic cirrhosis (p = 0.03). SCSD was found to be higher by PBMC-PCR in non-cirrhotics compared to cirrhotics (p = 0.0001), with an insignificant difference when using SRT-PCR (p = 0.45). Intra-PBMC HCV-RNA infection was significantly more frequent in cirrhotics compared to both non-cirrhotics and controls (p < 0.0005). An increased hepatic fibrosis density was recognized in intra-PBMC HCV-RNA infection with sense (p = 0.0001) or antisense strand (p = 0.003). HCV-RNA seroconversion was associated with intra-PBMC infection when both sense and antisense strands were detected (p = 0.047).

Conclusions: Intracellular HCV-RNA evaluation is crucial for diagnosing OCIs and addressing relapse probability.

Cholangitis is a serious life-threatening situation affecting the hepatobiliary system. This review provides an update regarding the clinical and pathological features of various forms of cholangitis. A comprehensive search was performed in the PubMed, Scopus, and Web of Knowledge databases. It was found that the etiology and pathogenesis of cholangitis are heterogeneous. Cholangitis can be categorized as primary sclerosing (PSC), secondary (acute) cholangitis, and a recently characterized form, known as IgG4-associated cholangitis (IAC). Roles of genetic and acquired factors have been noted in development of various forms of cholangitis. PSC commonly follows a chronic and progressive course that may terminate in hepatobiliary neoplasms. In particular, PSC commonly has been associated with inflammatory bowel disease. Bacterial infections are known as the most common cause for AC. On the other hand, IAC has been commonly encountered along with pancreatitis. Imaging evaluation of the hepatobiliary system has emerged as a crucial tool in the management of cholangitis. Endoscopic retrograde cholangiography, magnetic resonance cholangiopancreatography and endoscopic ultrasonography comprise three of the modalities that are frequently exploited as both diagnostic and therapeutic tools. Biliary drainage procedures using these methods is necessary for controlling the progression of cholangitis. Promising results have been reported for the role of antibiotic treatment in management of AC and PSC; however, immunosuppressive drugs have also rendered clinical responses in IAC. With respect to the high rate of complications, surgical interventions in patients with cholangitis are generally restricted to those patients in whom other therapeutic approaches have failed.

Background and Aims: Given the increased risk of post-transplant metabolic syndrome (PTMS; defined by hypertension, diabetes mellitus and hyperlipidemia), we aimed to identify the potential role of food addiction in the development of metabolic complications in the post-liver transplant population.

Methods: Inclusion criteria included adult liver transplant recipients followed at our institution between June 2016 and November 2016. Participants were administered a demographic survey as well as the Yale Food Assessment Scale 2.0, a 35-item questionnaire used to assess frequency of food addiction in accordance with the DSM-V guidelines of substance use disorders. Demographic and clinical data were collected.

Results: Our study included 236 liver transplant recipients (139 males, 97 females). The median (interquartile range [IQR]) BMI of participants was 26.8 kg/m2 (24.2, 30.4), and median (IQR) time since transplantation was 50.9 months (19.6, 119.8). The prevalence rates of hypertension, hypercholesterolemia and diabetes mellitus were 54.7%, 25.0% and 27.1%, respectively. Twelve participants (5.1%) were found to have a diagnosis of food addiction. A diagnosis of food misuse was made in 94 (39.8%) of the transplant recipients.

Conclusions: Our findings are consistent with prior data that indicate high prevalence of metabolic complications among liver transplant recipients. Food addiction was not predictive of metabolic complications within this population. Nevertheless, we found that this population was at high risk of demonstrating symptoms of food misuse, and they were not likely to appreciate the risks of pathologic patterns of eating. Given the increasing risk of cardiovascular morbidity and mortality in this population, efforts should be made to identify risk factors for the development of PTMS.

Alcoholic hepatitis (AH) is an acute inflammatory liver disease with poor prognosis. Infections in AH are difficult to detect and contribute to short-term mortality. Intrahepatic cholestasis and elevated alkaline phosphatase levels are also associated with worse outcomes. This report describes an uncommon presentation of severe AH.

We report an atypical case of salicylate toxicity in a child without a reported exposure to aspirin, who presented with coexisting methemoglobinemia and carboxyhemoglobinemia, and provide mechanistic theories as to the potential pathway by which salicylates can lead to such dyshemoglobinemias. The patient, a 17-month old male, presented to the hospital 10 h after six episodes of vomiting, tachypnea and hyperpnea. Laboratory values showed a mixed respiratory alkalosis and metabolic acidosis; however, the parent’s denial of aspirin exposure, coupled with laboratory results indicating carboxyhemoglobinemia, methemoglobinemia and neutrophilic leukocytosis, disguised a toxic salicylate level of 51.1 mg/dL. We searched the PubMed database for sources of salicylate exposure using the terms: “salicylate exposure”, “salicylate toxicity”, “sources”, and an association of salicylates with carboxyhemoglobinemia methemoglobinemia using those three terms. Furthermore, Google Scholar and PubMed were used to search for biochemical literature explaining the association of salicylates with red blood cell oxidation, methemoglobin and carbon monoxide formation. We discovered that the mechanism by which high dose salicylates lead to carboxyhemoglobinemia and methemoglobinemia had not been previously described. We propose that salicylates in high doses can induce a methemoglobinemia through increased vascular release of nitric oxide through induction of IL-1β and carboxyhemoglobinemia via lipid peroxidation, leading to the release of carbon monoxide.

Hepatitis C (HCV) infection has an estimated global prevalence of 2.5%, causing chronic liver disease in 170 million people worldwide. Recent data has identified HCV infection as a risk factor for subclinical and clinical cardiovascular disease (CVD), but these data have been mixed and whether HCV is an independent risk factor for development of CVD remains controversial. In this review, we present the literature regarding the association of HCV with subclinical and clinical CVD and the possible underlying mechanisms leading to increased CVD among those infected with HCV. HCV infection leads to increased CVD via direct and indirect mechanisms with chronic inflammation, endothelial dysfunction and direct invasion of the arterial wall cited as possible mechanisms. Our review showed that HCV infection, particularly chronic HCV infection, appears to lead to increased subclinical CVD most consistently and potentially also to increased clinical CVD outcomes, leading to increased morbidity and mortality. Furthermore, the majority of studies evaluating the impact of HCV therapy on CVD morbidity and mortality showed an improvement in subclinical and clinical CVD endpoints in patients who were successfully treated and achieved sustained viral suppression. These results are of particular interest following the development of new direct antiviral agents which have made HCV eradication simple and feasible for many more patients globally, and in doing so may possibly reduce CVD morbidity and mortality in those with chronic HCV infection.

Medicinal plants are the richest, cheapest and most readily available source of drugs, nutraceuticals and food supplements. Pharmaceutical industries still rely largely on medicinal plants for intermediates due to their chemical diversities. This study, therefore, investigated the chemical constituents, thermal decomposition products and biological activities of extract from seeds of Cola nitida (the ‘kola nut’).

The pulverized seed was sequentially extracted with dichloromethane and methanol CH3OH. The extracts were analysed directly by Fourier Transform Infra-Red, electrospray ionization mass spectrometer and as fatty acid methyl ester and trimethylsilyl derivatives by gas chromatography-mass spectrometry (GC-MS). The CH3OH extract was analysed by high-performance liquid chromatography for sugars. The intact and extracted seed biomasses were analysed directly by pyrolysis GC-MS. For isolation of chemicals and assessment of biological activity, a large scale CH3OH extraction was performed and the extract partitioned with n-hexane, ethyl acetate (EtOAc) and butanol. Fractionation was done using various chromatographic techniques. Antimicrobial and antioxidant activities of the extract, fractions and isolated caffeine were respectively determined by the methods of agar-well diffusion and 2,2-diphenyl-1-picrylhydrazyl radical scavenging.

Caffeine and hexadecanoic acid were isolated from the EtOAc fraction while theobromine, caffeine, catechins, procyanidins, proanthocyanidins, sugars, fatty acids, alcohols and sterols were identified in the extracts. Multitude (62) biomass degradation products were identified in pyrolysed seed samples. The extract and fractions showed varying activities against most of the tested microbes, except against Shigella species, for which neither the extract nor fractions elicited any response. The butanol fraction exhibited the highest antioxidant activity.

This report gives insight into the chemical constituents in Cola nitida seed, details the thermal decomposition constituents and establishes the antimicrobial and antioxidant activities of the seed extract and fractions, thereby contributing to the knowledge on the chemistry and pharmacology of the genus.

Cannabis has been used medicinally for centuries and numerous species of this genus are undoubtedly amongst the primeval plant remedies known to humans. Cannabis sativa in particular is the most reported species, due to its substantial therapeutic implications that are owed to the presence of chemically and pharmacologically diverse cannabinoids. These compounds have long been used for the palliative treatment of cancer. Recent advancements in receptor pharmacology research have led to the identification of cannabinoids as effective antitumor agents. This property is accredited for their ability to induce apoptosis, suppress proliferative cell signalling pathways and promote cell growth inhibition. Evolving lines of evidence suggest that cannabinoid analogues, as well as their receptor agonists, may offer a novel strategy to treat various forms of cancer. This review summarizes the historical perspective of C. sativa, its potential mechanism of action, and pharmacokinetic and pharmacodynamic aspects of cannabinoids, with special emphasis on their anticancer potentials.

Background and Aims: Direct-acting antiviral (DAA) therapy is the cornerstone of the treatment of chronic hepatitis C virus (HCV) infection. Eradication of HCV, predicted by the attainment of a sustained virologic response (SVR) 12 weeks following DAA therapy, is the goal of this treatment. Interestingly, recent studies have reported the possible association between HCV-infected patients with DAA therapy concomitant use of proton pump inhibitors (PPIs) and lower odds of achieving SVR. This meta-analysis was conducted to summarize all available data and to estimate this potential association.

Methods: Comprehensive literature review was conducted by first searching the Medline and Embase databases through March 2017 to identify all studies that investigated the safety and efficacy of DAAs in patients with HCV infection taking PPIs versus those without PPIs. Adjusted point estimates from each study were combined by the generic inverse variance method of DerSimonian and Laird.

Results: Nine cohort studies with 32,684 participants met the eligibility criteria and were included in the meta-analysis. The use of PPIs concomitant with DAAs among HCV-infected patients was associated with lower odds of achieving SVR compared with non-PPI users (pooled odds ratio (OR): 0.74, 95% confidence interval (CI): 0.63–0.88, I2 = 24%). Subgroup analysis addressed the association between PPIs use and SVR12 demonstrated the association of PPI users showing lower odds of achieving SVR12 compared with those with no use of PPIs (pooled OR: 0.68, 95% CI: 0.51–0.9, I2 = 33%).

Conclusions: This study demonstrated a significantly increased risk of failure to achieve SVR in HCV-infected patients taking DAA with PPIs compared to non-PPI users. Providers should consider whether PPI therapy is indicated for patients and withdraw of PPI therapy in the absence of indications, especially while on DAA therapy.

Hepatitis E is the fifth known form of human viral hepatitis. Although not very common in our clinical practice, the incidence in Western countries is increasing. Infection with the hepatitis E virus (HEV) may be related to acute illness, liver failure, chronic hepatitis and cirrhosis. HEV itself is an RNA virus, with eight described genotypes (HEV 1–8), four of which more commonly affect humans and have, thus, been better studied. Besides liver manifestations, genotype 3 is also related to extra-hepatic manifestations, such as neurological, renal and rheumatological. Evolution to chronic disease occurs especially in patients who underwent transplantation, have hematological malignancies requiring chemotherapy, or have infection with the human immunodeficiency virus. The diagnosis may be difficult because of the low availability of tests and due to low sensibility and specificity. The acute form of illness does not have to be treated, but the chronic one does. We present here a literature review of hepatitis E and the relation between chronic hepatitis E and transplantation.

Metformin is key in the management of type 2 diabetes mellitus but also represents additional financial burden, particularly with the use of branded products. The availability of generic products permits generic substitution with a much-reduced cost of treatment. However, only generic products that offer similar bioavailability with the innovator should be considered. This study was designed to assess the bioequivalence of generic metformin tablets within Nigeria.

Metformin tablets selected from the Nigerian market were appraised for quality following British and United States Pharmacopoeia guidelines. In vivo bioequivalence study in healthy volunteers was applied for a generic and the innovator brand in an open-label, 2-arm, 2-treatment crossover fashion with a 1-week washout period. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h post-dose. Plasma concentrations of metformin were analysed using a validated high-performance liquid chromatography method, and pharmacokinetic parameters were obtained using the non-compartmental approach. The formulations were considered bioequivalent based on the guidelines by United States Food and Drug Administration, Centre for Drug Evaluation and Research.

Nine generic products met the quality assessment standards, and the in vivo bioequivalence study was carried out in 17 healthy volunteers. The mean values for Cmax, Tmax, AUC0–24, and AUC0–∞ for the innovator brand of metformin were 0.43 ± 0.14 µg/mL, 1.35 ± 0.46 h, 2.03 ± 0.68 µg/mL* h and 2.63 ± 1.11 µg/mL* h respectively; for the generic product, the values were 0.44 ± 0.13 µg/mL, 1.41 ± 0.59 h, 2.04 ± 0.68 µg/mL* h and 2.85 ± 1.37 µg/mL*h. The 90% confidence intervals for the test formulation/reference formulation ratio for Log Cmax, Log AUC0–10 hr and AUC0–∞ were within the bioequivalence limits of 80% to 125% (95.8–106.8, 94.8–105.5 and 96.3–108.4 respectively).

The bioavailability of the test product was not inferior to innovator metformin.