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.

Sirenomelia (otherwise known as Mermaid Syndrome), is a very rare congenital anomaly characterized by variable fusion of lower limbs along with thoracolumbar spinal anomalies, sacrococcygeal agenesis, genitourinary and gastrointestinal tract malformations, with an incidence of 0.8 to 1 case per 100,000 births. This anomaly has a strong association with maternal diabetes, and some researchers consider it to be a severe form of caudal regression syndrome. It is a lethal anomaly, with half of the cases being stillborn and most cases involving live births dying within a few days. We present here a radiological evaluation of a case of sirenomelia in a 28-year-old primigravida with history of occasional cocaine and alcohol use. The fetus had duodenal atrasia, bilateral renal agenesis, caudal dysgenesis, imperforate anus and absent genitalia, as determined by fetal sonogram and fetal magnetic resonance imaging (MRI), which had been carried out for better evaluation. Fetal sonogram revealed sacral dysgenesis, and double bubble sign suggestive of duodenal atresia. Fetal MRI showed bilateral renal agenesis, duodenal atresia and single hypoplastic lower limb. One of two upper limbs was also found to be hypoplastic. After delivery, the stillborn was examined externally. There were no external genitalia and the anus was imperforate. There was a single hypoplastic lower limb. One of two upper limbs was also hypoplastic. Early diagnosis of sirenomelia is necessary for safe termination of pregnancy. However, complete evaluation of a sirenomelia fetus is hindered by associated severe oligohydramnios. Fetal MRI has no such constraints and can demonstrate various anomalies in a greater detail than fetal sonogram.

Evaluation of the extent and progression of liver fibrosis and cirrhosis is of critical importance in the management and prognosis of patients with chronic hepatitis B. Due to the limitation of liver biopsy, non-invasive methods, especially liver stiffness measurement (LSM) by vibration controlled transient elastography, have been developed and widely applied for liver fibrosis assessment. LSM aims to reduce, but not to substitute, the need for liver biopsy for fibrosis/cirrhosis diagnosis. While LSM may have potential utility in monitoring treatment response, its applications in prediction of liver complications in terms of portal hypertension and esophageal varices, as well as disease prognosis, have been gradually validated. Here, we review the latest clinical applications of LSM in patients with chronic hepatitis B.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in developed countries because of the obesity epidemic. The disease increases liver-related morbidity and mortality, and often increases the risk for other comorbidities, such as type 2 diabetes and cardiovascular disease. Insulin resistance related to metabolic syndrome is the main pathogenic trigger that, in association with adverse genetic, humoral, hormonal and lifestyle factors, precipitates development of NAFLD. Biochemical markers and radiological imaging, along with liver biopsy in selected cases, help in diagnosis and prognostication. Intense lifestyle changes aiming at weight loss are the main therapeutic intervention to manage cases. Insulin sensitizers, antioxidants, lipid lowering agents, incretin-based drugs, weight loss medications, bariatric surgery and liver transplantation may be necessary for management in some cases along with lifestyle measures. This review summarizes the latest evidence on the epidemiology, natural history, pathogenesis, diagnosis and management of NAFLD.

Accumulating evidence suggests that dysfunction within the endocannabinoid (eCB) system may play a role in psychosis. However, little is understood about how this may be related to the neurocognitive abnormalities and symptoms of psychosis. In this paper, we summarize some of the evidence supporting the role of eCB system in psychosis, as well as the current understanding of the neurocognitive underpinnings of psychosis. We particularly focus on neuroimaging evidence pertaining to alteration in the functional integration between different brain regions in patients with psychosis, and then relate this to evidence from neuroimaging studies of the effects of cannabis and its main ingredients, such as delta-9-tetrahydrocannainol and cannabidiol. Specifically, we explore this in the context of the hypothesis that psychosis is a disorder of dysconnectivity between different brain regions, focusing particularly on three large scale functional networks (the default mode, central executive, and salience networks), alterations in which have been implicated in psychosis, and we discuss the gaps in this research thus far. Finally, we propose that an approach to investigating the role of the eCB system in psychosis may be to employ a pharmacological cannabinoid challenge paradigm to examine how experimental perturbation of the eCB system may be related to abnormalities in the brain networks implicated in psychosis. We discuss challenges associated with this approach, and suggest safe and practical options to overcome the main issues involved with such an experimental approach. Studies employing such an approach have the potential of offering insight into the neurocognitive mechanisms underlying psychosis, and identifying novel therapeutic targets.

Liver transplantation (LT) has become standard of care in patients with non-resectable early stage hepatocellular carcinoma (HCC) in liver cirrhosis. Currently, patient selection for LT is strictly based on tumor size and number, provided by the Milan criteria. This may, however, exclude patients with advanced tumor load but favourable biology from a possibly curative treatment option. It became clear in recent years that biological tumor viability rather than tumor macromorphology determines posttransplant outcome. In particular, microvascular invasion and poor grading reflect tumor aggressiveness and promote the risk of tumor relapse. Pretransplant biopsy is not applicable due to tumor heterogeneity and risk of tumor cell seeding. 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET), an established nuclear imaging device in oncology, was demonstrated to non-invasively correlate with unfavorable histopathologic features. Currently, there is an increasing amount of evidence that 18F-FDG-PET is very useful for identifying eligible liver transplant patients with HCC beyond standard criteria but less aggressive tumor properties. In order to safely expand the HCC selection criteria and the pool of eligible liver recipients, tumor evaluation with 18F-FDG-PET should be implemented in pretransplant decision process.

Hepatitis B is a significant public health problem in India, yet disease awareness is very low among the general population. The disease is mostly acquired horizontally, but the role of vertical transmission should not be underestimated. In spite of the fact that the majority of cases are e negative disease, most patients present in the advanced stage and even with hepatocellular carcinoma, the leading cause of which is hepatitis B. High-risk groups (especially tribals) also harbour significant disease burden and have a high prevalence of occult infection, supporting the potential of unknowingly spreading the disease. Findings on the relation of genotypes with disease severity or drug action have been conflicting. Though recently, oral antivirals with high genetic barrier to resistance have shown good viral suppression in the long term, e and s seroconversion is poor and relapse is universal upon therapy discontinuation. As no cure is possible with the currently available therapy, the target is long-term viral suppression by prolonged administration of oral antivirals; unfortunately, this leads to poor treatment adherence, which along with the high cost of therapy results in disease progression and spread of infection. At present, therefore, emphasis should be put on health education of the general and high-risk populations, along with health care workers to increase knowledge on such preventive measures as avoiding unsafe injection practices, high-risk sex, performing unnecessary injection and blood transfusion and providing proper screening of blood products; these efforts should be combined with intensive screening and aggressive vaccination programs, especially in high-risk groups and areas of high endemicity. Vaccination strategies are still below par and logistics should be developed for wider coverage; in addition, further research should be carried out on the efficacy and mode of usage for different types of vaccine.

Background and Aims: There has been increasing evidence that vitamin D deficiency may increase the risk of metabolic syndrome. Since metabolic syndrome is a major risk factor for non-alcoholic fatty liver disease (NAFLD), we aimed to investigate the association between vitamin D and the severity and mortality of NAFLD.

Methods: Data was obtained from the United States Third National Health and Nutrition Examination Survey conducted in 1988–1994, with follow-up mortality data through 2011. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases and categorized as normal, mild, moderate or severe. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). ANOVA (F-test) was used to evaluate the association between vitamin D level and degree of NAFLD, and Cox proportional hazards regression analysis was used for survival analyses.

Results: Vitamin D levels for normal, mild, moderate and severe steatosis were 25.1 ± 0.29 ng/mL, 24.7 ± 0.42 ng/mL, 23.7 ± 0.37 ng/mL and 23.6 ± 0.60 ng/mL, respectively (trend p < 0.001). Likewise, vitamin D levels for low, intermediate and high NFS categories were 24.7 ± 0.38 ng/mL, 23.4 ± 0.42 ng/mL and 21.5 ± 0.57 ng/mL, respectively (trend p < 0.001). After median-follow up over 19 years, vitamin D deficiency was significantly associated with diabetes- and Alzheimer’s disease-related mortality (hazard ratio (HR): 3.64, 95%CI: 1.51–8.82 and HR: 4.80, 95%CI: 1.53–15.1, respectively), with a borderline significance in overall mortality (HR: 1.16, 95%CI: 0.99–1.36, p = 0.06).

Conclusions: Vitamin D level was inversely related to the degree of liver steatosis and fibrosis. Moreover, vitamin D deficiency was associated with diabetes- and Alzheimer’s disease-related mortality in NAFLD patients.

Background and Aims: A visual analogue score (VAS), based on application of a visual analogue scale, has been widely used to assess pruritus in clinical studies of patients with cholestatic liver disease. A VAS is a numerical score of the severity of the perception of pruritus, and, hence, is inherently subjective. The objective of this study was to assess the reliability of a VAS as an index of pruritus in cholestatic patients.

Methods: In 8 patients with chronic pruritus due to primary biliary cholangitis, values for a VAS of pruritus were compared with corresponding measurements of scratching activity, which were generated by a monitoring system specifically designed to quantitate this activity. The relationship between individual values for the VAS and corresponding values for scratching activity during a specific interval immediately preceding the recording of the VAS was examined by determining the Spearman’s rank correlation coefficient.

Results: The mean Spearman’s rank correlation coefficient between individual values for the VAS and corresponding mean values for scratching activity was 0.072; the range of these coefficients was −0.04 to 0.26. A VAS of pruritus is an unreliable index of scratching activity, and, hence, of the pathophysiological process responsible for the pruritus of cholestasis.

Conclusions: It is concluded that the use of a VAS as a primary quantitative endpoint in trials of the efficacy of potential therapies for the pruritus of cholestasis may be inappropriate.

Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach.

Infections account for significant morbidity and mortality in liver cirrhosis and most are related to the gut microbiome. Fecal dysbiosis, characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous non-pathogenic bacteria, becomes prominent with the progression of liver cirrhosis. In cirrhotic patients, disruption of the intestinal barrier causes intestinal hyperpermeability (i.e. leaky gut), which is closely related to gut dysmotility, dysbiosis and small intestinal bacterial overgrowth and may induce pathological bacterial translocation. Although the involved microbial taxa are somewhat different between the cirrhotic patients from the East and the West, the common manifestation of a shortage of bacteria that contribute to the production of short-chain fatty acids and secondary bile acids may facilitate intestinal inflammation, leaky gut and gut dysbiosis. Translocated endotoxin and bacterial DNA are capable of provoking potent inflammation and affecting the metabolic and hemodynamic systems, which may ultimately enhance the progression of liver cirrhosis and its various complications, such as hepatic encephalopathy (HE), variceal bleeding, infection and renal disturbances. Among studies on the microbiome-based therapeutics, findings of probiotic effects on HE have been contradictory in spite of several supportive results. However, the effects of synbiotics and prebiotics are substantially documented. The background of their effectiveness should be evaluated again in relation to the cirrhosis-related changes in gut microbiome and their metabolic effects. Strict indications for the antibiotic rifaximin remain unestablished, although its effect is promising, improving HE and other complications with little influence on microbial populations. The final goal of microbiome-based therapeutics is to adjust the gut-liver axis to the maximal benefit of cirrhotic patients, with the aid of evolving metagenomic and metabolomic analyses.

Acetaminophen is the active metabolite of phenacetin, a weak inhibitor of COX-1 and COX-2 in peripheral tissues, and it is one of the most widely prescribed drugs in pediatrics, used to weaken fever and to attenuate pain. Different formulations and dosages are available on the market. Division of the suppository form is a widely-used technique and it allows for optimization of the dosage based on the weight of the child. Yet, few data are available in the literature about the effectiveness of this practice. The aim of this study was to evaluate the uniformity of distribution of acetaminophen inside the suppository and to verify the homogeneity of distribution after the division.

Two hundred and twenty-four suppositories of different batches, dosages and producers were examined (Tachipirina®, Efferalgan®). One half of the suppositories (n=112) were divided by the same operator in two halves along the vertical axis, and the other half (n=112) were not divided but only weighed. In each of the groups (whole and fractional), the suppositories were evaluated by weight, acetaminophen content and the uniformity of the acetaminophen distribution.

In no case did the partition of the suppositories led to significant differences (t-test) between weight of the head and tail portion. No significant differences in weight, acetaminophen content or acetaminophen distribution of the active component were present in any of the two halves of the total suppositories analyzed after the partition.

Splitting acetaminophen suppositories is a common practice and it is a convenient medical procedure, with low chance of error, and it should not raise concerns of accurate dosage.

Neonatal, cardiac and pediatric intensive care units (ICUs) frequently use the neurally adjusted ventilatory assist (NAVA) mode of ventilation, which has been shown to improve patient-ventilator synchrony and decrease work of breathing as it uses neural impulse to guide patient and ventilator breaths. We reviewed uses of NAVA as the mode of ventilation and oxygenation in pediatric (P)ICU and cardiac (C)ICU patients. We found that NAVA mode improves patient-ventilator interaction by improving synchrony and thus decreasing work of breathing. This eventually improved all aspects of critical care, as demonstrated by decreased need for sedation, improvement in hemodynamics, improvement in patient comfort, decreased days on ventilator, decreased days in ICU and decreased hospital length of stay. Additional studies need to be done in order to help NAVA technology become a primary mode of ventilation in PICU and CICU. Further studies are also needed to evaluate the successful use of noninvasive-NAVA as a means of preventing endotracheal intubation or to allow early extubation in our population.

In recent years, it has become recognized that patients with eosinophilic esophagitis (EoE) have an increased risk of multiple autoimmune diseases. Possible shared genetic aetiologies have been observed between EoE and autoimmune diseases. Currently, it is believed that EoE is not associated with a higher risk of neoplasms since such published cases are very rare and there are only isolated reports. Herein, we describe a unique case of EoE due to gluten without coeliac disease. The patient presented some unusual comorbidities, such as hypothyroidism (autoimmune disease) and essential thrombocythemia (neoplasm of haematologic origin).

Non-alcoholic fatty liver disease (NAFLD) is a burgeoning global health concern. In the subset of NAFLD patients with non-alcoholic steatohepatitis (NASH), the presence of significant fibrosis at index assessment is associated with poor prognosis and increased mortality. Hence, there is a growing need to accurately assess and stage fibrosis. Liver biopsy, the current gold standard, has limitations with sampling error and is invasive, with associated inherent risk. This has led to a host of non-invasive means of assessing fibrosis, which has garnered relevance in a disease that requires serial assessment of fibrosis longitudinally over time. This review discusses, comprehensively, the various tools available to the clinician for the assessment of fibrosis, including the various scoring systems used in liver biopsy, the non-invasive means of serum biomarkers, such as the highly-validated NAFLD fibrosis score, and the imaging-based modalities, such as transient elastography and magnetic resonance elastography.