Effects of Aspen Phenolic Glycosides on Gypsy Moth (Lepidoptera: Lymantriidae) Susceptibility to \u3ci\u3eBacillus Thuringiensis\u3c/i\u3e

Performance of the gypsy moth, Lymantria dispar, on quaking aspen, Populus tremuloides, is strongly affected by foliar concentrations of phenolic glycosides. Because the microbial insecticide Bacillus thuringiensis is widely used against gypsy moths and has a mode of action similar to that of phenolic glycosIdes, we investigated the combined effects of the two toxins on gypsy moth larvae. The experimental design was a 2 x 2 factorial: two levels (0, +) of phenolicglycosides for each of two levels (0, +) of B. thuringiensis. The toxins were incorporated into artificial diets and bioassayed against first and fourth instars. Bacillus thuringiensis and phenolic glycosides ne~atively and addi· tively affected larval survival, growth and development tImes. Both agents slightly reduced consumption rates. In addition, B. thuringiensis reduced diet digestibility whereas phenolic glycosides decreased the efficiency with which food was converted to biomass. These results suggest that the efficacy of B. thuringiensis applications in aspen forests is likely to be affected by the allelo· chemical composition of foliage

Acute Alcohol-Induced Liver Injury

Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD) in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation, and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, which also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic

Hypoxia promotes liver stage malaria infection in primary human hepatocytes in vitro

Homeostasis of mammalian cell function strictly depends on balancing oxygen exposure to maintain energy metabolism without producing excessive reactive oxygen species. In vivo, cells in different tissues are exposed to a wide range of oxygen concentrations, and yet in vitro models almost exclusively expose cultured cells to higher, atmospheric oxygen levels. Existing models of liver stage malaria that utilize primary human hepatocytes typically exhibit low in vitro infection efficiencies, possibly due to missing microenvironmental support signals. One cue that may influence the infection capacity of cultured human hepatocytes is the dissolved oxygen concentration. We developed a microscale human liver platform comprised of precisely patterned primary human hepatocytes and nonparenchymal cells (MPCC) to model liver stage malaria, but the oxygen concentrations are typically higher in the in vitro liver platform than anywhere along the hepatic sinusoid. Indeed, we observed that liver stage Plasmodium parasite development in vivo correlates with hepatic sinusoidal oxygen gradients. Therefore, we hypothesized that in vitro liver stage malaria infection efficiencies may improve under hypoxia. Using the infection of MPCCs with P. berghei or P. yoelii as a model, we observed that ambient hypoxia resulted in increased survival of exo-erythrocytic forms (EEFs) in hepatocytes, and improved parasite development in a subset of surviving EEFs, based on EEF size. Further, the effective cell surface oxygen tensions (pO2) experienced by the hepatocytes, as predicted by a mathematical model, were systematically perturbed by varying culture parameters like hepatocyte density and media height, uncovering an optimal cell surface pO2 to maximize the number of mature EEFs. Initial mechanistic experiments reveal that treatment of primary human hepatocytes with the hypoxia mimetic, cobalt (II) chloride, as well as a HIF-1α activator, dimethyloxalylglycine, also enhance P. berghei infection, suggesting that the effect of hypoxia on infection is mediated in part by host-dependent HIF-1α mechanisms.Bill & Melinda Gates Foundation (Award 51066)Howard Hughes Medical Institut

Transitional Remodeling of the Hepatic Extracellular Matrix in Alcohol-Induced Liver Injury

Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well understood. The liver is the primary site of alcohol metabolism and is therefore the major target of alcohol toxicity. Alcoholic liver disease is a spectrum of disease states, ranging from simple steatosis (fat accumulation), to inflammation, and eventually to fibrosis and cirrhosis if untreated. The fibrotic stage of ALD is primarily characterized by robust accumulation of extracellular matrix (ECM) proteins (collagens) which ultimately impairs the function of the organ. The role of the ECM in early stages of ALD is poorly understood, but recent research has demonstrated that a number of changes in the hepatic ECM in prefibrotic ALD not only are present, but may also contribute to disease progression. The purpose of this review is to summarize the established and proposed changes to the hepatic extracellular matrix (ECM) that may contribute to earlier stages of ALD development and to discuss potential mechanisms by which these changes may mediate the progression of the disease

Value of schizophrenia treatment I:The patient journey

BackgroundThe aim of the European Brain Council project “The Value of Treatment” was to provide evidence-based, cost-effective policy recommendations for a patient-centered and sustainable coordinated care model for brain disorders. The first part of schizophrenia study examined the needs and gaps in the patients' care pathway.MethodsDescriptive analysis was based on an inventory of needs and treatment opportunities, using focus group sessions, expert interviews, users’ input, and literature review. Three patient pathways were selected: indicated prevention, duration of untreated psychosis, and relapse prevention.ResultsThe analysis identified several critical barriers to optimal treatment. Available health care services often miss or delay detection of symptoms and diagnosis in at-risk individuals. There is a lack of illness awareness among patients, families, and the public; scarcity of information, training and education among primary care providers; stigmatizing beliefs. Early symptom recognition and timely intervention result in better outcome and prognosis; effective management leads to a functional recovery. In the current model of care, there is insufficient cooperation between health and social care providers, patients and families, inadequate utilization of pharmacological and psychosocial interventions, lacking patient monitoring, and low implementation of integrated community care.ConclusionsEarly detection and early intervention programs, timely intervention, and relapse prevention are essential for effective management of schizophrenia. It requires a paradigm shift from symptom control, achieving and maintaining remission, to the emphasis on recovery. Since the current services are not able to accomplish this goal, changes in mental health policies are needed

Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse.

Aim: Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury. Methods: C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage. Results: BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals (P \u3c 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (alpha-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals (P \u3c 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug (P \u3c 0.05). Conclusion: The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury