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BACKGROUND & AIMS Augmenter of liver regeneration (ALR, encoded by GFER) is a widely distributed pleiotropic protein originally identified as a hepatic growth factor. However, little is known about its roles in hepatic physiology and pathology. We created mice with liver-specific deletion of ALR to study its function. METHODS We developed mice with liver-specific deletion of ALR (ALR-L-KO) using the albumin-Cre/LoxP system. Liver tissues were collected from ALR-L-KO mice and ALRfloxed/floxed mice (controls) and analyzed by histology, reverse-transcription PCR, immunohistochemistry, electron microscopy, and techniques to measure fibrosis and lipids. Liver tissues from patients with and without advanced liver disease were determined by immunoblot analysis. RESULTS Two weeks after birth, livers of ALR-L-KO mice contained low levels of ALR and ATP; they had reduced mitochondrial respiratory function and increased oxidative stress, compared with livers from control mice, and had excessive steatosis, and hepatocyte apoptosis. Levels of carbamyl-palmitoyl transferase 1a and ATP synthase subunit ATP5G1 were reduced in livers of ALR-L-KO mice, indicating defects in mitochondrial fatty acid transport and ATP synthesis. Electron microscopy showed mitochondrial swelling with abnormalities in shapes and numbers of cristae. From weeks 2–4 after birth, levels of steatosis and apoptosis decreased in ALR-L-KO mice, whereas numbers of ALR-expressing cells increased, along with ATP levels. However, at weeks 4–8 after birth, livers became inflamed, with hepatocellular necrosis, ductular proliferation, and fibrosis; hepatocellular carcinoma developed by 1 year after birth in nearly 60% of the mice. Hepatic levels of ALR were also low in ob/ob mice and alcohol-fed mice with liver steatosis, compared with controls. Levels of ALR were lower in liver tissues from patients with advanced alcoholic liver disease and nonalcoholic steatohepatitis than in control liver tissues. CONCLUSIONS We developed mice with liver-specific deletion of ALR, and showed that it is required for mitochondrial function and lipid homeostasis in the liver. ALR-L-KO mice provide a useful model for investigating the pathogenesis of steatohepatitis and its complications.

Study findings build to a multi-axial strategy for measuring personality disorder, involving separate dimensional assessment of both disordered personality function and of personality style.

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The immunogenicity of the conjugate prepared from "processed" a-subunit of human chorionic gonadotropin (choriogonadotropin, HCG) and tetanus toxoid has been studied in animals and a human subject. The conjugate elicited the formation of high-affinity (Ka = 109-101' M-') anti-HCG and anti-tetanus antibodies. On primary immunization, the antibody response lasted for several months. Repeat injection of the conjugate in the declining phase of antibody titers produced a booster response without a lag period. The antibodies reacted with the ,8-subunit of HCG and the complete HCG molecule but were devoid of significant crossreactivity with human growth hormone, placental lactogen, follicle-stimulating hormone, thyroid-stimulating hormone, and luteinizing hormone at tonic and surge levels. The antibodies were competent for neutralizing the biological activity of HCG in the mouse uterine weight gain assay, the ventral prostate weight gain assay, and the radioligand assay for binding of 1251-labeled HCG to receptors on corpus luteum. HCG (5000 international units) administered to an immunized subject was completely bound by circulating antibodies. Administration of HCG (in contrast to conjugate) was without booster effect on anti-HCG titers.

Background:There are very few studies from India which have evaluated the prescription pattern for antidepressants by psychiatrists for treatment of depression.Aim:To study the psychotropic prescription patterns of patients with first episode depression from diverse settings including teaching institutions in public and private sectors and even privately run psychiatric clinics.Materials and Methods:Prescription data of 706 patients with first episode depression, who participated in the IPS multicentric study, were evaluated.Results:Escitalopram was the most commonly prescribed antidepressant, comprising 40% of the total prescriptions. This was followed by sertraline (17.6%) and fluoxetine (16.3%). In total, selective serotonin reuptake inhibitors (SSRIs) formed 79.2% of all the prescriptions. Tricyclic antidepressants formed a small part (15.15%) of total prescriptions, with imipramine being the most commonly used tricyclic antidepressant. Serotonin-norepinephrine reuptake inhibitors (venlafaxine, desvenlafaxine and duloxetine) were prescribed to 11.3% of patients with equal share of venlafaxine and duloxetine. About one-sixth (N=104; 14.7%) of the patients were prescribed more than one antidepressant. Nearly three-fourth of the patients (N=523; 74.1%) were prescribed a benzodiazepine, with clonazepam being the most preferred agent, prescribed to nearly half of the participants (49%) and formed nearly two-third of the total benzodiazepine prescriptions (346 out of 523).Conclusion:Escitalopram is the most commonly prescribed antidepressant and SSRIs are the most commonly prescribed class of antidepressants. Poly pharmacy in the form of concomitant use of two antidepressants is practiced infrequently. However, benzodiazepines are used quite frequently as the co-prescription.

Gram-negative bacterial endotoxin lipopolysaccharide (LPS) is implicated in acute and chronic liver injury; its effects are mediated predominantly via the membrane receptor Toll-like receptor 4 (TLR4). However, TLR4-independent effects of LPS may play important role in hepatic pathophysiology. We investigated carbon tetrachloride (CCl)-induced fibrosis and LPS-induced acute liver injury in wild-type (WT) and B6.B10ScN-Tlr4/JthJ [TLR4-knockout (KO)] mice. Effects of LPS on fibrogenic hepatic stellate cells (HSCs) from WT and TLR4-KO mice were assessed in vitro. CCl produced similar fibrosis and necroinflammation and increased the mRNA and protein expression of cytokines and chemokines in WT and TLR4-KO mice. However, circulating LPS concentration did not increase in CCl-treated mice. Interestingly, LPS down-modulated α-smooth muscle actin (activated HSC marker) and collagen 1 in both WT and TLR4-KO HSCs. LPS induced similar activation of NF-κB, and stimulated the expression of cytokines and chemokines in WT and TLR4-KO HSCs. Finally, LPS caused similar inflammation and injury in previously untreated WT and TLR4-KO mice. The results provide evidence of the TLR4/LPS-independent mechanisms of liver fibrosis and also indicate that TLR4 is not entirely critical to LPS-induced acute liver injury. The results further indicate that LPS signaling in activated HSCs might be a mechanism of limiting liver fibrosis.