Environmental enrichment alters neurobehavioral development following maternal immune activation in mice offspring with epilepsy.

Epilepsy is a chronic brain disease affecting millions of people worldwide. Anxiety-related disorders and cognitive deficits are common in patients with epilepsy. Previous studies have shown that maternal infection/immune activation renders children more vulnerable to neurological disorders later in life. Environmental enrichment has been suggested to improve seizures, anxiety, and cognitive impairment in animal models. The present study aimed to explore the effects of environmental enrichment on seizure scores, anxiety-like behavior, and cognitive deficits following maternal immune activation in offspring with epilepsy. Pregnant mice were treated with lipopolysaccharides-(LPS) or vehicle, and offspring were housed in normal or enriched environments during early adolescence to adulthood. To induce epilepsy, adult male and female offspring were treated with Pentylenetetrazol-(PTZ), and then anxiety-like behavior and cognitive functions were assessed. Tumor-necrosis-factor (TNF)-α and interleukin (IL) 10 were measured in the hippocampus of offspring. Maternal immune activation sex-dependently increased seizure scores in PTZ-treated offspring. Significant increases in anxiety-like behavior, cognitive impairment, and hippocampal TNF-α and IL-10 were also found following maternal immune activation in PTZ-treated offspring. However, there was no sex difference in these behavioral abnormalities in offspring. Environmental enrichment reversed the effects of maternal immune activation on behavioral and inflammatory parameters in PTZ-treated offspring. Overall, the present findings highlight the adverse effects of prenatal maternal immune activation on seizure susceptibility and psychiatric comorbidities in offspring. This study suggests that environmental enrichment may be used as a potential treatment approach for behavioral abnormalities following maternal immune activation in PTZ-treated offspring.

Senescence and the SASP: many therapeutic avenues.

Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.

Susceptibility of Rat Steatotic Liver to Ischemia-Reperfusion Is Treatable With Liver-Selective Matrix Metalloproteinase Inhibition.

BACKGROUND AND AIMS: This study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury. APPROACH AND RESULTS: Hepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis. CONCLUSIONS: Lack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

Characteristics and dispositional determinants of psychiatric emergencies in a University Hospital in Beirut.

Mental health problems are common in Lebanon, and so are psychiatric emergencies. In order to show the characteristics of psychiatric emergencies in Lebanon along with their dispositional determinants, we conducted this retrospective, single-center, chart-review study of patients who presented to the Emergency Department between July 1, 2016 until December 31, 2016 and required an official psychiatrist consultation. Our sample included 195 patients of all age groups. The most common diagnosis was depression (75 patients) followed by anxiety (61 patients). 107 patients (54.8%) required admission for adequate treatment; however only 72 (67.3%) of those were actually admitted, and the rest (32.7%) left the hospital against medical advice. Increased hospital admission was associated with being a female (OR = 3.042), having family history of psychiatric disease (OR = 2.040) and having suicidal ideations (OR = 12.949). In a country that has inadequate health coverage, financial coverage can also be a determining factor in whether or not patients get the admission they need.

Microbiome-wide association studies link dynamic microbial consortia to disease.

Rapid advances in DNA sequencing, metabolomics, proteomics and computational tools are dramatically increasing access to the microbiome and identification of its links with disease. In particular, time-series studies and multiple molecular perspectives are facilitating microbiome-wide association studies, which are analogous to genome-wide association studies. Early findings point to actionable outcomes of microbiome-wide association studies, although their clinical application has yet to be approved. An appreciation of the complexity of interactions among the microbiome and the host's diet, chemistry and health, as well as determining the frequency of observations that are needed to capture and integrate this dynamic interface, is paramount for developing precision diagnostics and therapies that are based on the microbiome.

Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation.

BACKGROUND: Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation. OBJECTIVE: The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (INa) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion. METHODS: In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 µg/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/kg IV bolus over 15 minutes). RESULTS: Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, Tpeak-Tend interval by 74%) and atrial repolarization alternans (TWAa) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P = .007), T-wave heterogeneity by 23% (P = .035), and Tpeak-Tend by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWAa by 64% (P = .002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P <.001), JT interval by 8% (P <.001), and atrial action potential duration (PTa) by 8% (P = .002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P = .054). CONCLUSION: Selective inhibition of cardiac late INa with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects.

Intense pulsed light enhances transforming growth factor beta1/Smad3 signaling in acne-prone skin.

BACKGROUND: Recently, much interest has been generated in the use of intense pulsed light (IPL) sources in the treatment of various skin conditions. However, the underlying mechanism for its therapeutic action has not been elucidated. OBJECTIVE: To investigate the effect of IPL on the in vivo expression of transforming growth factor beta1 (TGF-ß1) and on the immunolocalization of Smad3 in biopsies obtained from perilesional skin in patients with mild-to-moderate inflammatory acne vulgaris. METHODS: Biopsies obtained from 20 patients with inflammatory acne vulgaris at baseline (B1) and post-IPL treatment (B2 = 48 h after first treatment and B3 = 1 week after final treatment) were immunohistochemically analyzed to determine the expression of TGF-ß1 and the immunolocalization of Smad3. Digital images were semiquantitatively assessed using image analysis software. RESULTS: Intense pulsed light elicited a consistent increase in epidermal TGF-ß1 expression (B2 vs. B1: P = 0.004 and B3 vs. B1: P = 0.007). Furthermore, it resulted in enhanced nuclear immunolocalization of Smad3 (B2 vs. B1: epidermis, P = 0.000055 and dermis, P = 0.014; B3 vs. B1: epidermis, P = 0.00024 and dermis, P = 0.008). CONCLUSION: Intense pulsed light upregulates TGF-ß1/Smad3 signaling in perilesional skin obtained from patients with mild-to-moderate inflammatory acne vulgaris. Further experiments on lesional skin and downstream effects are warranted to determine whether it may play a role in IPL-induced resolution of acne vulgaris.

Effects of ginger supplementation on cell-cycle biomarkers in the normal-appearing colonic mucosa of patients at increased risk for colorectal cancer: results from a pilot, randomized, and controlled trial.

To estimate the effects of ginger on apoptosis, proliferation, and differentiation in the normal-appearing colonic mucosa, we randomized 20 people at increased risk for colorectal cancer to 2.0 g of ginger or placebo daily for 28 days in a pilot trial. Overall expression and distributions of Bax, Bcl-2, p21, hTERT, and MIB-1 (Ki-67) in colorectal crypts in rectal mucosa biopsies were measured using automated immunohistochemistry and quantitative image analysis. Relative to placebo, Bax expression in the ginger group decreased 15.6% (P = 0.78) in the whole crypts, 6.6% (P = 0.95) in the upper 40% (differentiation zone) of crypts, and 21.7% (P = 0.67) in the lower 60% (proliferative zone) of crypts; however, there was a 19% increase (P = 0.14) in Bax expression in the upper 40% relative to the whole crypt. While p21 and Bcl-2 expression remained relatively unchanged, hTERT expression in the whole crypts decreased by 41.2% (P = 0.05); the estimated treatment effect on hTERT expression was larger in the upper 40% of crypts (-47.9%; P = 0.04). In the ginger group, MIB-1 expression decreased in the whole crypts, upper 40% of crypts, and lower 60% of crypts by 16.9% (P = 0.39), 46.8% (P = 0.39), and 15.3% (P = 0.41), respectively. These pilot study results suggest that ginger may reduce proliferation in the normal-appearing colorectal epithelium and increase apoptosis and differentiation relative to proliferation--especially in the differentiation zone of the crypts and support a larger study to further investigate these results.

Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy.

Triheptanoin is a triglyceride containing heptanoate, an odd-chained medium fatty acid that is metabolized to produce propionyl-CoA and subsequently C4 intermediates of the citric acid cycle and therefore capable of anaplerosis. These metabolic products are believed to underlie triheptanoin's anticonvulsant effects in rodent seizure models. Here we investigate the anticonvulsive effects of oral triheptanoin in a syndrome-specific genetic mouse model of generalized epilepsy based on the GABA(A)γ2(R43Q) mutation. Mice were fed a diet supplemented with triheptanoin from weaning for three weeks prior to electrocortical recordings. Occurrence and durations of spike and wave discharges (SWDs) were measured. Triheptanoin did not alter body weight or basal blood glucose levels suggesting that it was well tolerated. Triheptanoin supplementation halved the time spent in seizures due to a reduction in both SWD occurrence and duration. An injection of insulin was used to reduce blood glucose, a metabolic stress known to precipitate seizures in the GABA(A)γ2(R43Q) mouse. The reduction in seizure count was also evident following insulin induced hypoglycemia with the triheptanoin treated group having significantly less SWDs than control animals under similar low blood glucose conditions. In summary, triheptanoin may be an effective and well tolerated dietary therapy for generalized epilepsy.

NK cells in hepatitis C: role in disease susceptibility and therapy.

Hepatitis C is caused by infection with the hepatitis C virus (HCV), a single-stranded RNA virus, which was first described in 1989. Hepatitis C is a major global health burden with approximately 150 million people chronically infected worldwide. Chronic HCV infection is a main cause of liver cirrhosis and hepatocellular carcinoma. Current treatment of hepatitis C is based on the administration of peg-IFN-α and ribavirin. However, this therapy can be associated with severe side effects. The role of NK cells in the pathogenesis of acute and chronic liver disease in HCV infection has only been studied in recent years, but those studies indicate an important role for this cell type. NK cells are a major component of the innate arm of the immune system. We summarize the current knowledge on NK cell phenotype and function in acute and chronic HCV infection. Moreover, we discuss the role of NK cells in IFN-α-based antiviral therapy. Understanding the mode of function and role of NK cells during HCV infection and therapy will become even more important in the near future, when new IFN-α-free treatment regimens become available.

[Role of psychosocial stress in complex diseases]. / Rôle du stress psychosocial dans les maladies complexes.

Complex diseases are chronic diseases where the interrelations between genetic predisposition and environmental factors play an essential role in the arisen and the maintenance of the pathology. Upon psychological stress, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are activated resulting in release of glucocorticoids and catecholamines. Chronic stress may induce complex diseases where alterations of nervous, endocrine and immune systems are involved. Thus, chronic stress is more likely to induce a range of effects, depending on the capacity of the subject to cope with stress. CRH ("Corticotropin Releasing Hormone") is a key factor in the stress-immunity relationship. In this article, we propose an overview of the interrelations between central nervous, endocrine and immune systems and implications for health and diseases. The objective for the clinician is to propose therapeutic strategies targeting changes in human behaviour to cope with a potentially stressful environment.

Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction.

OBJECTIVES: The aim of this study was to evaluate the links between connexin43 (Cx43) expression, myocardial conduction velocity, and ventricular tachycardia in a model of healed myocardial infarction. BACKGROUND: Post-infarction ventricular arrhythmias frequently cause sudden death. Impaired myocardial conduction has previously been linked to ventricular arrhythmias. Altered connexin expression is a potential source of conduction slowing identified in healed scar border tissues. The functional effect of increasing border-zone Cx43 has not been previously evaluated. METHODS: Twenty-five Yorkshire pigs underwent anterior infarction by transient left anterior descending coronary artery occlusion, followed by weekly testing for arrhythmia inducibility. Twenty animals with reproducibly inducible sustained monomorphic ventricular tachycardia were randomized 2:1:1 to receive AdCx43, Adßgal, or no gene transfer. One week later, animals underwent follow-up electrophysiologic study and tissue assessment for several functional and molecular measures. RESULTS: Animals receiving AdCx43 had less electrogram fractionation and faster conduction velocity in the anterior-septal border zone. Only 40% of AdCx43 animals remained inducible for ventricular tachycardia, while 100% of controls were inducible after gene transfer. AdCx43 animals had 2-fold higher Cx43 protein levels in the anterior-septal infarct border, with similar percents of phosphorylated and intercalated disk-localized Cx43 compared with controls. CONCLUSIONS: These data mechanistically link Cx43 expression to slow conduction and arrhythmia susceptibility in the healed scar border zone. Targeted manipulation of Cx43 levels improved conduction velocity and reduced ventricular tachycardia susceptibility. Cx43 gene transfer represents a novel treatment strategy for post-infarction arrhythmias.

Human disease modeling with induced pluripotent stem cells.

In the past few years, cellular programming, whereby virtually all human cell types, including those deep within the brain or internal organs, can potentially be produced and propagated indefinitely in culture, has opened the door to a new type of disease modeling. Importantly, many diseases or disease predispositions have genetic components that vary from person to person. Now cells from individuals can be readily reprogrammed to form pluripotent cells, and then directed to differentiate into the lineage and the cell type in which the disease manifests. Those cells will contain the genetic contribution of the donor, providing an excellent model to delve into human disease at the level of individuals and their genomic variants. To date, over fifty such disease models have been reported, and while the field is young and hurdles remain, these tools promise to inform scientists about the cause and cellular-molecular mechanisms involved in pathology, unravel the role of environmental versus hereditary factors driving disease, and provide an unprecedented tool for screening therapeutic agents that might slow or halt disease progression.

A co-module approach for elucidating drug-disease associations and revealing their molecular basis.

MOTIVATION: Understanding how drugs and diseases are associated in the molecular level is of critical importance to unveil disease mechanisms and treatments. Until recently, few studies attempt end to discover important gene modules shared by both drugs and diseases. RESULTS: Here, we propose a novel presentation of drug-gene-disease relationship, a 'co-module', which is characterized by closely related drugs, diseases and genes. We first define a network-based gene closeness profile to relate drug to disease. Then, we develop a Bayesian partition method to identify drug-gene-disease co-modules underlying the gene closeness data. Genes share similar notable patterns with respect not only to the drugs but also the diseases within a co-module. Simulations show that our method, comCIPHER, achieves a better performance compared with a popular co-module detection method, PPA. We apply comCIPHER to a set consisting of 723 drugs, 275 diseases and 1442 genes and demonstrate that our co-module approach is able to identify new drug-disease associations and highlight their molecular basis. Disease co-morbidity emerges as well. Three co-modules are further illustrated in which new drug applications, including the anti-cancer metastasis activity of an anti-asthma drug Pranlukast, and a cardiovascular stress-testing agent Arbutamine for obesity, as well as potential side-effects, e.g. hypotension for Triamterene, are computationally identified. AVAILABILITY: The compiled version of comCIPHER can be found at http://bioinfo.au.tsinghua.edu.cn/comCIPHER/. The 86 co-modules can be downloaded from http://bioinfo.au.tsinghua.edu.cn/comCIPHER/Co_Module_Results.zip. CONTACT: shaoli@mail.tsinghua.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Myelin-associated glycoprotein protects neurons from excitotoxicity.

In addition to supporting rapid nerve conduction, myelination nurtures and stabilizes axons and protects them from acute toxic insults. One myelin molecule that protects and sustains axons is myelin-associated glycoprotein (MAG). MAG is expressed on the innermost wrap of myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the glycosylphosphatidylinositol-anchored Nogo receptors, and ß1-integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag-null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag-null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin NMDA. Prior injection of a soluble form of MAG partially protected Mag-null mice from NMDA-induced lesions. Hippocampal neurons plated on proteins extracted from wild-type rat or mouse myelin were resistant to kainic acid-induced excitotoxicity, whereas neurons plated on proteins from Mag-null myelin were not. Protection was reversed by anti-MAG antibody and replicated by addition of soluble MAG. MAG-mediated protection from excitotoxicity was dependent on Nogo receptors and ß1-integrin. We conclude that MAG engages membrane-domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.

Notions of synergy for combinations of interventions against infectious diseases in heterogeneously mixing populations.

In public health programmes interventions are frequently combined with hoped for 'synergies'[22]. However, there is not yet a precise definition for synergy between interventions that captures the idea that there is added benefit at the population-level in using them together. To explore the synergy between interventions in the context of endemic disease, we consider a general model of infection spread in a heterogeneously mixing population. We consider interventions which may alter individuals' infectiousness, susceptibility, profile of infectiousness through time and survival while infected. Allowing general patterns of overlap and targeting in those receiving the interventions, we show how to compute changes to epidemiological indices such as R(0), and introduce a simple technique for calculating equilibrium prevalences and incidences via an iterated map. We argue for a particular definition of synergy and investigate its behaviour, both analytically and numerically, concluding that it is easiest to achieve synergy between interventions which perform poorly in isolation; implementation strategies that minimize the overlap of different interventions in the population tend to achieve more synergy; and that in populations with heterogeneous risk, interventions that are redundant when universally targeted can regain substantial synergy when applied in a targeted manner.

The Ezrin-radixin-moesin family member ezrin regulates stable microtubule formation and retroviral infection.

We recently identified the cytoskeletal regulatory protein moesin as a novel gene that inhibits retroviral replication prior to reverse transcription by downregulation of stable microtubule formation. Here, we provide evidence that overexpression of ezrin, another closely related ezrin-radixin-moesin (ERM) family member, also blocks replication of both murine leukemia viruses and human immunodeficiency virus type 1 (HIV-1) in Rat2 fibroblasts before reverse transcription, while knockdown of endogenous ezrin increases the susceptibility of human cells to HIV-1 infection. Together, these results suggest that ERM proteins may be important determinants of retrovirus susceptibility through negative regulation of stable microtubule networks.