Non-alcoholic fatty liver disease associated with hypobetalipoproteinemia: report of three cases and a novel mutation in APOB gene

Background: Non-alcoholic fatty liver disease, the leading cause of chronic liver disease in children, is defined by hepatic fat infiltration >5% of hepatocytes, in the absence of excessive alcohol intake, evidence of viral, autoimmune or drug-induced liver disease. Conditions like rare genetic disorders must be considered in the differential diagnosis. Case Report: Two male brothers, and a non-related girl, all overweight, had liver steatosis. One of the brothers and the girl had elevated transaminases; all three presented with low total cholesterol, low density lipoproteins and very low density lipoproteins cholesterol levels, hypotriglyceridemia and low apolipoprotein B. A liver biopsy performed in the brother with citolysis confirmed steatohepatitis and the molecular study of apolipoprotein B gene showed a novel homozygous mutation (c.9353dup p.Asn3118Lysfs17). Patients with cytolysis lost weight, however liver steatosis persists. Conclusion: Fatty liver disease might be a consequence of hypobetalipoproteinemia. Evidence is scarce due to low number of reported cases.

Prospective associations between meth/amphetamine (speed) and MDMA (ecstasy) use and depressive symptoms in secondary school students

Background Research has raised significant concern regarding the affective consequences of synthetic drug use. However, little evidence from well-controlled longitudinal studies exists on these consequences. The aim of this study was to determine whether use of meth/amphetamine (speed) and 63,4- methylenedioxymethamphetamine (MDMA, ecstasy) is independently predictive of subsequent depressive symptoms in adolescents. Methods A sample of 3880 adolescents from secondary schools in disadvantaged areas of Quebec, Canada, were followed over time (2003e2008). Logistic regression was used to test the association between meth/ amphetamine and MDMA use in grade 10 (ages 15e16 years) and elevated depressive symptoms on an abridged Center for Epidemiologic Studies-Depression scale in grade 11, controlling for pre-existing individual and contextual characteristics. Results After adjustment, both MDMA use (OR 1.7, 95% CI 1.1 to 2.6) and meth/amphetamine use (OR 1.6, 95% CI 1.1 to 2.3) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. These relationships did not vary by gender or pre-existing depressive symptoms. Increased risk was particularly observed in concurrent usage (OR 1.9, 95% CI 1.2 to 2.9). Conclusions Adolescent use of meth/amphetamine and MDMA (particularly concurrent use) is independently associated with subsequent depressive symptoms. Further enquiry must determine whether these associations reflect drug-induced neurotoxicity and whether adolescence is a period of increased vulnerability to the hazards of synthetic drug exposure.

Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model.

The current chemotherapeutic treatment of alveolar echinococcosis (AE) in humans is based on albendazole and/or mebendazole. However, the costs of treatment, life-long consumption of drugs, parasitostatic rather than parasiticidal activity of chemotherapy, and high recurrence rates after treatment interruption warrant more efficient treatment options. Experimental treatment of mice infected with Echinococcus multilocularis metacestodes with fenbendazole revealed similar efficacy to albendazole. Inspection of parasite tissue from infected and benzimidazole-treated mice by transmission electron microscopy (TEM) demonstrated drug-induced alterations within the germinal layer of the parasites, and most notably an almost complete absence of microtriches. On the other hand, upon in vitro exposure of metacestodes to benzimidazoles, no phosphoglucose isomerase activity could be detected in medium supernatants during treatment with any of these drugs, indicating that in vitro treatment did not severely affect the viability of metacestode tissue. Corresponding TEM analysis also revealed a dramatic shortening/retraction of microtriches as a hallmark of benzimidazole action, and as a consequence separation of the acellular laminated layer from the cellular germinal layer. Since TEM did not reveal any microtubule-based structures within Echinococcus microtriches, this effect cannot be explained by the previously described mechanism of action of benzimidazoles targeting β-tubulin, thus benzimidazoles must interact with additional targets that have not been yet identified. In addition, these results indicate the potential usefulness of fenbendazole for the chemotherapy of AE.

A synthetic biology-based device prevents liver injury in mice

BACKGROUND & AIMS The liver performs a panoply of complex activities coordinating metabolic, immunologic and detoxification processes. Despite the liver's robustness and unique self-regeneration capacity, viral infection, autoimmune disorders, fatty liver disease, alcohol abuse and drug-induced hepatotoxicity contribute to the increasing prevalence of liver failure. Liver injuries impair the clearance of bile acids from the hepatic portal vein which leads to their spill over into the peripheral circulation where they activate the G-protein-coupled bile acid receptor TGR5 to initiate a variety of hepatoprotective processes. METHODS By functionally linking activation of ectopically expressed TGR5 to an artificial promoter controlling transcription of the hepatocyte growth factor (HGF), we created a closed-loop synthetic signalling network that coordinated liver injury-associated serum bile acid levels to expression of HGF in a self-sufficient, reversible and dose-dependent manner. RESULTS After implantation of genetically engineered human cells inside auto-vascularizing, immunoprotective and clinically validated alginate-poly-(L-lysine)-alginate beads into mice, the liver-protection device detected pathologic serum bile acid levels and produced therapeutic HGF levels that protected the animals from acute drug-induced liver failure. CONCLUSIONS Genetically engineered cells containing theranostic gene circuits that dynamically interface with host metabolism may provide novel opportunities for preventive, acute and chronic healthcare. LAY SUMMARY Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage.

Prospective associations between meth/amphetamine (speed) and MDMA (ecstasy) use and depressive symptoms in secondary school students

Background Research has raised significant concern regarding the affective consequences of synthetic drug use. However, little evidence from well-controlled longitudinal studies exists on these consequences. The aim of this study was to determine whether use of meth/amphetamine (speed) and 63,4- methylenedioxymethamphetamine (MDMA, ecstasy) is independently predictive of subsequent depressive symptoms in adolescents. Methods A sample of 3880 adolescents from secondary schools in disadvantaged areas of Quebec, Canada, were followed over time (2003e2008). Logistic regression was used to test the association between meth/ amphetamine and MDMA use in grade 10 (ages 15e16 years) and elevated depressive symptoms on an abridged Center for Epidemiologic Studies-Depression scale in grade 11, controlling for pre-existing individual and contextual characteristics. Results After adjustment, both MDMA use (OR 1.7, 95% CI 1.1 to 2.6) and meth/amphetamine use (OR 1.6, 95% CI 1.1 to 2.3) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. These relationships did not vary by gender or pre-existing depressive symptoms. Increased risk was particularly observed in concurrent usage (OR 1.9, 95% CI 1.2 to 2.9). Conclusions Adolescent use of meth/amphetamine and MDMA (particularly concurrent use) is independently associated with subsequent depressive symptoms. Further enquiry must determine whether these associations reflect drug-induced neurotoxicity and whether adolescence is a period of increased vulnerability to the hazards of synthetic drug exposure.

Teratologic effects of long-term exposure to diesel exhaust emissions (rabbits) /

"Contract no. 68-03-2652."

Steatosis: Co-factor in other liver diseases

The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol- and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinernia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis.

Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin

Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)(1A) and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose ( 115 mg/kg) and high-dose ( 250 mg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration ( the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC ( altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem oscillator in perceptual rivalry alternations and symptoms of psychosis.

Is cannabis use a contributory cause of psychosis?

Objective: To assess whether cannabis use in adolescence and young adulthood is a contributory cause of schizophreniform psychosis in that it may precipitate psychosis in vulnerable individuals. Method: We reviewed longitudinal studies of adolescents and young adults that examined the relations between self-reported cannabis use and the risk of diagnosis with a psychosis or of reporting psychotic symptoms. We also reviewed studies that controlled for potential confounders, such as other forms of drug use and personal characteristics that predict an increased risk of psychosis. We assessed evidence for the biological plausibility of a contributory causal relation. Results: Evidence from 6 longitudinal studies in 5 countries shows that regular cannabis use predicts an increased risk of a schizophrenia diagnosis or of reporting symptoms of psychosis. These relations persisted after controlling for confounding variables, such as personal characteristics and other drug use. The relation did not seem to be a result of cannabis use to self-medicate symptoms of psychosis. A contributory causal relation is biologically plausible because psychotic disorders involve disturbances in the dopamine neurotransmitter systems with which the cannabinoid system interacts, as demonstrated by animal studies and one human provocation study. Conclusion: It is most plausible that cannabis use precipitates schizophrenia in individuals who are vulnerable because of a personal or family history of schizophrenia.

The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier

Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.

Bioequivalence of sustained release theophylline formulations

The bioequivalence of sustained release theophylline formulations, marketed in the United Kingdom, has been investigated in relation to the co-administration of food in both single dose and steady state volunteer studies. The effect of food on pharmacokinetic parameters and their clinical relevance was researched. Experimentation using drug induced modification of gastric motility to ascertain the component influences of the rate of gastric emptying on the absorption of theophylline from sustained release formulations was conducted. Prolongation of time to maximum plasma theophylline concentration by food reported in the literature and its clinical importance was investigated in once daily compared with twice daily administration of sustained release theophylline formulations and smoking habit. The correlation between saliva and plasma theophylline concentrations as a means of developing a non-invasive sampling techniques was examined. Data obtained from in vitro dissolution studies was compared with in vivo results. This thesis has shown no significant differences occurred in the pharmacokinetic parameters measured between sustained release formulations available in the United Kingdom. The investigations into the influence of food on prolongation of time to maximum plasma theophylline concentration and other measured pharmacokinetic parameters demonstrated no important pharmacokinetic or clinical effects. Smoking adults taking sustained release theophylline formulations had similar drug clearances to those reported in the literature for smokers taking plain uncoated theophylline formulations. KEY WORDS Bioequivalence Theophylline Sustained Release Food Pharmacokinetics RONALD PURKISS SUBMITTED FOR

Functional characterisation of Schistosoma japonicum acetylcholinesterase

BACKGROUND: Acetylcholinesterase (AChE) is an important metabolic enzyme of schistosomes present in the musculature and on the surface of the blood stage where it has been implicated in the modulation of glucose scavenging from mammalian host blood. As both a target for the antischistosomal drug metrifonate and as a potential vaccine candidate, AChE has been characterised in the schistosome species Schistosoma mansoni, S. haematobium and S. bovis, but not in S. japonicum. Recently, using a schistosome protein microarray, a predicted S. japonicum acetylcholinesterase precursor was significantly targeted by protective IgG1 immune responses in S. haematobium-exposed individuals that had acquired drug-induced resistance to schistosomiasis after praziquantel treatment.

RESULTS: We report the full-length cDNA sequence and describe phylogenetic and molecular structural analysis to facilitate understanding of the biological function of AChE (SjAChE) in S. japonicum. The protein has high sequence identity (88 %) with the AChEs in S. mansoni, S. haematobium and S. bovis and has 25 % sequence similarity with human AChE, suggestive of a highly specialised role for the enzyme in both parasite and host. We immunolocalized SjAChE and demonstrated its presence on the surface of adult worms and schistosomula, as well as its lower expression in parenchymal regions. The relatively abundance of AChE activity (90 %) present on the surface of adult S. japonicum when compared with that reported in other schistosomes suggests SjAChE may be a more effective drug or immunological target against this species. We also demonstrate that the classical inhibitor of AChE, BW285c51, inhibited AChE activity in tegumental extracts of paired worms, single males and single females by 59, 22 and 50 %, respectively, after 24 h incubation with 200 μM BW284c51.

CONCLUSIONS: These results build on previous studies in other schistosome species indicating major differences in the enzyme between parasite and mammalian host, and provide further support for the design of an anti-schistosome intervention targeting AChE.

Extracellular vesicle biogenesis in helminths: more than one route to the surface?

The quite recent discovery that parasites release extracellular vesicles (EVs) that can transfer a range of effector molecules to host cells has made us re-think our understanding of the host-parasite interface. In this opinion article we will consider how recent proteomics and transcriptomics studies, together with ultrastructural observations, suggest that more than one mechanism of EV biogenesis can occur in helminths. We propose that distinct EV sub-types have roles in immune-modulation and repair of drug-induced damage, and put forward the case for targeting EV biogenesis pathways to achieve parasite control. In doing so we raise a number of outstanding research questions that must be addressed before this can happen.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

The Influence of Estrogens on the Biological and Therapeutic Actions of Growth Hormone in the Liver

[EN]GH is main regulator of body growth and composition, somatic development, intermediate metabolism and gender-dependent dimorphism in mammals. The liver is a direct target of estrogens because it expresses estrogen receptors which are connected with development, lipid metabolism and insulin sensitivity, hepatic carcinogenesis, protection from drug-induced toxicity and fertility. In addition, estrogens can modulate GH actions in liver by acting centrally, regulating pituitary GH secretion, and, peripherally, by modulating GHR-JAK2-STAT5 signalling pathway