Surface Engineering of the Mechanical Properties of Molecular Crystals via an Atomistic Model for Computing the Facet Stress Response of Solids.

Invited for the cover of this issue are Mubarak Almehairbi, Vikram C. Joshi, Changquan Calvin Sun and Sharmarke Mohamed. The image depicts the digital exploration of the mechanical properties of crystals on specific facets that may be of interest for materials applications by "dialing-in" their stress response. Read the full text of the article at 10.1002/chem.202400779.

Surface Engineering of the Mechanical Properties of Molecular Crystals via an Atomistic Model for Computing the Facet Stress Response of Solids.

Dynamic molecular crystals are an emerging class of crystalline materials that can respond to mechanical stress by dissipating internal strain in a number of ways. Given the serendipitous nature of the discovery of such crystals, progress in the field requires advances in computational methods for the accurate and high-throughput computation of the nanomechanical properties of crystals on specific facets which are exposed to mechanical stress. Here, we develop and apply a new atomistic model for computing the surface elastic moduli of crystals on any set of facets of interest using dispersion-corrected density functional theory (DFT-D) methods. The model was benchmarked against a total of 24 reported nanoindentation measurements from a diverse set of molecular crystals and was found to be generally reliable. Using only the experimental crystal structure of the dietary supplement, L-aspartic acid, the model was subsequently applied under blind test conditions, to correctly predict the growth morphology, facet and nanomechanical properties of L-aspartic acid to within the accuracy of the measured elastic stiffness of the crystal, 24.53±0.56 GPa. This work paves the way for the computational design and experimental realization of other functional molecular crystals with tailor-made mechanical properties.

A Systematic Review of Frailty Scores Used in Heart Failure Patients.

BACKGROUND: Frailty is a complex, multi-dimensional syndrome commonly observed in patients with heart failure (HF). The presence of frailty in patients living with HF is strongly associated with increased vulnerability to adverse events, including falls, hospitalisation, and increased mortality. Several scoring systems have been developed to assess the presence of frailty in patients with HF. These scoring systems vary in their complexity and applicability; however, they provide the physician with a more comprehensive understanding of the biological, functional, and psychosocial needs of these patients. OBJECTIVES: To assess the clinical applicability of frailty tools in HF patients and their prognostic value, specifically relating to outcomes such as mortality, readmissions, and clinical deterioration. METHODS: A literature search using six electronic databases (PubMed, Scopus, Embase, MEDLINE, Cochrane and Web of Science) was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key search Medical Subject Headings (MeSH) terms combined "Frailty" AND "Heart failure". Studies were included if they assessed frailty using systematically defined criteria in a HF population. The PRISMA guidelines were used to include all relevant articles based on titles and abstracts. Full text articles were screened based on abstract relevance. A systematic narrative review of the literature was conducted on the final list of full text articles. RESULTS: An initial search yielded 8,066 articles. Following the removal of duplicates, title, and abstract searches, the remaining 154 articles underwent full text review, with 31 articles accepted for final qualitative synthesis. The two most utilised frailty scores were the Fried Frailty Phenotype (n=10) and the Barthel Index (n=8). The frailty scores provide prognostic data on multiple outcomes including mortality, increased hospitalisation, and functional decline. CONCLUSION: At the present time there is no universally applied frailty measure in a HF population. Choice of frailty score should be guided by physician experience and clinical setting, as well as tailored to a patient's functional, biological, and psychosocial circumstances. A push to adopt a single universal scoring system may help to ensure that frailty is assessed in all patients who live with HF.

Syringol isolated from Eleusine coracana (L.) Gaertn bran suppresses inflammatory response through the down-regulation of cPLA2, COX-2, IκBα, p38 and MPO signaling in sPLA2 induced mice paw oedema.

Eleusine coracana (L.) Gaertn (E. coracana) is one of the highest consuming food crops in Asia and Africa. E. coracana is a plant with several medicinal values including anti-ulcerative, anti-diabetic, anti-viral and anti-cancer properties. However, the anti-inflammatory property of E. coracana remains to be elucidated. Therefore, the objective of present study was to investigate the potential in isolated molecule from E. coracana via a combination of in vitro, in vivo and in silico methods. In this study, we have isolated, purified and characterized an anti-inflammatory molecule from E. coracana bran extract known as syringol. Purification of syringol was accomplished by combination of GC-MS and RP-HPLC techniques. Syringol significantly inhibited the enzymes activity of sPLA2 (IC50 = 3.00 µg) and 5-LOX (IC50 = 0.325 µg) in vitro. The inhibition is independent of substrate concentration, calcium ion concentration and was irreversible. Syringol interacts with purified sPLA2 enzymes as evidenced by fluorescence and molecular docking studies. Further, the syringol molecule dose dependently inhibited the development of sPLA2 and λ-carrageenan induced edema. Furthermore, syringol decreases the expression of cPLA2, COX-2, IκBα, p38 and MPO in edematous tissues as demonstrated by western blots. These studies revealed that syringol isolated from E. coracana bran may develop as a potent anti-inflammatory molecule.

Mechanotransduction in gastrointestinal smooth muscle cells: role of mechanosensitive ion channels.

Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiological reactions. Nonspecialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells use various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G protein-coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex-the ability of smooth muscle to contract in response to stretch rapidly-is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and mechanosensitive ion channels, which alter their ion pores' opening in response to force, allowing fast electrical and Ca2+ responses. Although GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and mechanosensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and mechanosensitive ion channels.

microRNA overexpression in slow transit constipation leads to reduced NaV1.5 current and altered smooth muscle contractility.

OBJECTIVE: This study was designed to evaluate the roles of microRNAs (miRNAs) in slow transit constipation (STC). DESIGN: All human tissue samples were from the muscularis externa of the colon. Expression of 372 miRNAs was examined in a discovery cohort of four patients with STC versus three age/sex-matched controls by a quantitative PCR array. Upregulated miRNAs were examined by quantitative reverse transcription qPCR (RT-qPCR) in a validation cohort of seven patients with STC and age/sex-matched controls. The effect of a highly differentially expressed miRNA on a custom human smooth muscle cell line was examined in vitro by RT-qPCR, electrophysiology, traction force microscopy, and ex vivo by lentiviral transduction in rat muscularis externa organotypic cultures. RESULTS: The expression of 13 miRNAs was increased in STC samples. Of those miRNAs, four were predicted to target SCN5A, the gene that encodes the Na+ channel NaV1.5. The expression of SCN5A mRNA was decreased in STC samples. Let-7f significantly decreased Na+ current density in vitro in human smooth muscle cells. In rat muscularis externa organotypic cultures, overexpression of let-7f resulted in reduced frequency and amplitude of contraction. CONCLUSIONS: A small group of miRNAs is upregulated in STC, and many of these miRNAs target the SCN5A-encoded Na+ channel NaV1.5. Within this set, a novel NaV1.5 regulator, let-7f, resulted in decreased NaV1.5 expression, current density and reduced motility of GI smooth muscle. These results suggest NaV1.5 and miRNAs as novel diagnostic and potential therapeutic targets in STC.

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

BACKGROUND: Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described. METHODS: Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discovered a novel persistent epigenetic mechanism of neurodegeneration in neonatal hippocampus and neocortex brain regions and of cognitive decline in adult animals. RESULTS: PEE, which activates caspase-3 (CC3, a neurodegeneration marker), enhanced histone deacetylase (HDAC1-HDAC3) levels and reduced histone 3 (H3) and 4 (H4) acetylation (ac) in mature neurons. PEE repressed the expression of several synaptic plasticity genes, such as brain-derived neurotrophic factor, C-Fos, early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Detailed studies on Egr1 and Arc expression revealed HDAC enrichment at their promoter regions. HDAC inhibition with trichostatin A (TSA) before PEE rescued H3ac/H4ac levels and prevented CC3 formation. Antagonism/null mutation of cannabinoid receptor type-1 (CB1R) before PEE to inhibit CC3 production prevented Egr1 and Arc loss via epigenetic events. TSA administration before PEE prevented postnatal ethanol-induced loss of Egr1 and Arc expression and neurobehavioral defects in adult mice via epigenetic remodeling. In adult mice, 3-day TSA administration attenuated PEE-induced behavioral defects. CONCLUSIONS: These findings demonstrate that CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression and is a critical step in fetal alcohol spectrum disorder-associated cognitive decline but is reversed by restoration of histone acetylation in the brain.

Endocannabinoid system in neurodegenerative disorders.

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

Predictors of success for double balloon-assisted endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y anastomosis.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with roux-en-Y anastomosis (REYA) is challenging. Use of double balloon enteroscope-assisted ERCP (DBE-ERCP) has been successful. We aim to determine predictors of successful biliary cannulation with DBE-ERCP in patients with REYA. METHODS: We retrospectively studied patients with REYA who had DBE-ERCP between 2009 and 2015. RESULTS: 86 DBE-ERCP were done on 52 patients. Patients had REYA for liver transplant (n = 26), gastrojejunostomy (n = 9), previous bile duct injury (n = 9), biliary atresia (n = 2) and other (n = 6). The biliary-enteric anastomosis was reached in 76% and cholangiogram was successful in 70%. Highest success rates were in patients with previous bile duct injury (94%) or gastrojejunostomy (89%). Post-transplant patients had intermediate success (64%). Patients with redo surgery (46%) and childhood surgery (38%), especially Kasai procedure (20%), had low success. Patients with previous bile duct injury were more likely to succeed (94% vs 63%, P = 0.010). Those more likely to fail were patients with childhood surgery (38% vs 73%, P = 0.037), biliary atresia (20% vs 73%, P = 0.013) and second operation post-transplant (25% vs 70%, P = 0.046). CONCLUSION: Indication for REYA impacts on successful biliary cannulation in patients undergoing DBE-ERCP. The procedure is most successful in non-liver transplant adult surgery and post-transplant patients without a second operation. It is least successful in patients with surgically corrected biliary atresia and post-transplant patients with second operation. Alternative methods of biliary access should be considered in these patients.

Dimethyl ester of bilirubin exhibits anti-inflammatory activity through inhibition of secretory phospholipase A2, lipoxygenase and cyclooxygenase.

Overproduction of arachidonic acid (AA) mediated by secretory phospholipase A2 group IIA (sPLA2IIA) is a hallmark of many inflammatory disorders. AA is subsequently converted into pro-inflammatory eicosanoids through 5-lipoxygenase (5-LOX) and cyclooxygenase-1/2 (COX-1/2) activities. Hence, inhibition of sPLA2IIA, 5-LOX and COX-1/2 activities is critical in regulating inflammation. We have previously reported unconjugated bilirubin (UCB), an endogenous antioxidant, as sPLA2IIA inhibitor. However, lipophilic UCB gets conjugated in liver with glucuronic acid into hydrophilic conjugated bilirubin (CB). Since hydrophobicity is pre-requisite for sPLA2IIA inhibition, conjugation reduces the efficacy of UCB. In this regard, UCB was chemically modified and derivatives were evaluated for sPLA2IIA, 5-LOX and COX-1/2 inhibition. Among the derivatives, BD1 (dimethyl ester of bilirubin) exhibited âˆ¼ 3 fold greater inhibitory potency towards sPLA2IIA compared to UCB. Both UCB and BD1 inhibited human 5-LOX and COX-2 activities; however only BD1 inhibited AA induced platelet aggregation. Molecular docking studies demonstrated BD1 as better inhibitor of aforesaid enzymes than UCB and other endogenous antioxidants. These data suggest that BD1 exhibits strong anti-inflammatory activity through inhibition of AA cascade enzymes which is of great therapeutic importance.

Celastrol modulates inflammation through inhibition of the catalytic activity of mediators of arachidonic acid pathway: Secretory phospholipase A2 group IIA, 5-lipoxygenase and cyclooxygenase-2.

Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2 group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol's ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50=6µM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50=5µM) and COX-2 (IC50=20µM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2 in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.

Albizia lebbeck seed methanolic extract as a complementary therapy to manage local toxicity of Echis carinatus venom in a murine model.

CONTEXT AND OBJECTIVE: Viperid venom-induced chronic local-toxicity continues even after anti-snake venom treatment. Therefore, traditional antidote Albizia lebbeck L. (Fabaceae) seed extract was tested against Echis carinatus S. (Viperidae) venom (ECV)-induced local toxicity to evaluate its complementary remedy. MATERIALS AND METHODS: Soxhlet extraction of A. lebbeck seeds was performed with the increasing polarity of solvents (n-hexane to water); the extract was screened for phytochemicals (alkaloids, anthraquinones, flavonoids, glycosides, phenolics, saponins, steroids and tannins). In preliminary in vitro analysis, A. lebbeck methanolic extract (ALME) demonstrated significant inhibition of ECV proteases, the major enzyme-toxin responsible for local- toxicity. Therefore, in vitro neutralizing potential of ALME was further evaluated against hyaluronidases and phospholipase A2 (1:1-1:100 w/w). In addition, alleviation of ECV induced characteristic local- toxicity [haemorrhage (i.d.) and myotoxicity (i.m.)] was determined in mice. RESULTS: ALME contained high concentrations of phenolics and flavonoids and demonstrated significant in vitro inhibition of ECV protease (IC50 = 36.32 µg, p < 0.0001) and hyaluronidase (IC50 = 91.95 µg, p < 0.0001) at 1:100 w/w. ALME significantly neutralized ECV induced haemorrhage (ED50 = 26.37 µg, p < 0.0001) and myotoxicity by significantly reducing serum creatinine kinase (ED50 = 37.5 µg, p < 0.0001) and lactate dehydrogenase (ED50 = 31.44 µg, p = 0.0021) levels at 1:50 w/w. DISCUSSION AND CONCLUSION: ALME demonstrated significant neutralization of ECV enzymes that contribute in local tissue damage and haemostatic alterations. The study scientifically supports the anecdotal use of A. lebbeck in complementary medicine and identifies ALME as principle fraction responsible for antivenom properties.

Tracking Gut Motility in Organ and Cultures.

Gastrointestinal (GI) motility is a key component of digestive health, and it is complex, involving a multitude of cell types and mechanisms to drive both rhythmic and arrhythmic activity. Tracking GI motility in organ and tissue cultures across multiple temporal (seconds, minutes, hours, days) scales can provide valuable information regarding dysmotility and to evaluate treatment options. Here, the chapter describes a simple method to monitor GI motility in organotypic cultures, using a single video camera is placed perpendicularly to the surface of the tissue. A cross-correlational analysis is used to track the relative movements of tissues between subsequent frames and subsequent fitting procedures to fit finite element functions to the deformed tissue to calculate the strain fields. Additional motility index measures from the displacement information are used to further quantify the behaviors of the tissues that are maintained in organotypic culture over days. The protocols presented in this chapter can be adapted to study organotypic cultures from other organs.

Microplastics as vectors of radioiodine in the marine environment: A study on sorption and interaction mechanism.

Radioiodine is one of the long-lived fission products and also an important radionuclide released during nuclear accidents, which generates interest in its environmental fate. Its sorption has been studied in a wide range of materials, but no equivalent study exists for microplastics, an emerging environmental vector. Weathering and biofilm formation on microplastics can enhance radioiodine sorption. For the first time, we're reporting how radioiodine interacts with different types of polyethylene derived microplastics (pristine, irradiated, and biofilm developed microplastics). This study revealed that exposure to radiation and the marine environment significantly alters the physico-chemical properties of microplastics. In particular, in marine-exposed samples, a signature of biofilm development was detected. Speciation study indicates that iodine exists in the iodide form in the studied marine environment. The study revealed that, iodide ions attach to biofilm-developed microplastics via electrostatic, ion-dipole, pore filling, and van der Waals interactions. Pore filling, ion-dipole, and van der Waals interactions may cause iodide binding to irradiated microplastics, whereas pore-filling and van der Waals interactions cause iodide binding to pristine microplastics. The distribution coefficient (Kd) of iodine on microplastics is positively correlated with biofilm biomass, which signifies the role of biofilm in radioiodine uptake. The Kd indicates microplastics are potential iodide accumulators and could be a possible vector in the marine system.

Insights into co-amorphous systems in therapeutic drug delivery.

Co-amorphous (CAM) systems are promising drug-delivery systems in the arena of therapeutic drug delivery, addressing the poor aqueous solubility of drugs by enhancing solubility and thereby improving the oral bioavailability and therapeutic effect of the drug. A CAM system is a single-phase homogeneous blend of two or more low molecular weight molecules that can be drug-drug or drug-co-former, stabilized via intermolecular interactions, adding the benefit of thermodynamic stability. This review covers the fundamentals of CAM systems and recent advances in formulation development. In particular, we strive to address the theoretical, molecular, technical and biopharmaceutical aspects, advantages over polymeric amorphous solid dispersions, mechanisms of stabilization of amorphous forms, insights into unexplored in silico tools in excipient selection and regulatory viewpoints.

Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems.

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.

CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol.

Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory, and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model.

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders.

Δ9 -tetrahydrocannabinol, the principal active component in Cannabis sativa extracts such as marijuana, participates in cell signalling by binding to cannabinoid CB1 and CB2 receptors on the cell surface. The CB1 receptors are present in both inhibitory and excitatory presynaptic terminals and the CB2 receptors are found in neuronal subpopulations in addition to microglial cells and astrocytes and are present in both presynaptic and postsynaptic terminals. Subsequent to the discovery of the endocannabinoid (eCB) system, studies have suggested that alcohol alters the eCB system and that this system plays a major role in the motivation to abuse alcohol. Preclinical studies have provided evidence that chronic alcohol consumption modulates eCBs and expression of CB1 receptors in brain addiction circuits. In addition, studies have further established the distinct function of the eCB system in the development of fetal alcohol spectrum disorders. This review provides a recent and comprehensive assessment of the literature related to the function of the eCB system in alcohol abuse disorders.

Immunity to Vaccine-preventable Viral Infections in Australians Being Evaluated for Liver Transplantation.

BACKGROUND: Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in immunocompromised patients. Current guidelines recommend routine screening and vaccination of all patients before solid organ transplantation. We studied rates of immunity against vaccine-preventable viruses in liver transplantation (LT) recipients. METHODS: We retrospectively studied consecutive adult patients who underwent first deceased donor LT at a single center between August 2008 and October 2017. Viruses studied were hepatitis A (HAV), hepatitis B (HBV), varicella zoster virus (VZV), measles, and mumps. Hepatitis B surface antibody (anti-HBs) <10 IU/mL in HBV surface antigen-negative patients and negative IgG to other viruses was regarded as absent immunity. RESULTS: Five hundred and fifty-five patients underwent LT (72.4% male; median age, 55.0 y). Percentages of patients who lacked immunity to vaccine-preventable infections were HAV (31.8%), HBV (63.8%), measles (1.4%), mumps (6.6%), and VZV (3.8%). Age was positively associated with immunity (from either past exposure or vaccination) against most viruses, including HAV, measles, mumps, and VZV (P < 0.05 for all). In contrast, older age was marginally associated with anti-HBs <10 IU/mL (P = 0.046). No significant changes in immunity rates were observed during the study period. CONCLUSIONS: A substantial number of patients undergoing LT are not immune to vaccine-preventable viruses at the time of assessment. This presents an opportunity for pre-LT vaccination and in particular younger patients may need to be targeted.