Search

Introduction: ACLF is characterized by acute deterioration of liver function in patients with chronic liver disease. HBV is one of the most important causes of both acute insult and underlying chronic liver disease in ACLF. Reactivation of HBV is one of the common causes of ACLF in our region. ACLF requires multiple organ support and is associated with high short and medium term mortality. This is the reason why early, rapid reduction of HBV DNA is essential in treating ACLF-B. Methods: Consecutive patients of ACLF-B due to spontaneous reactivation of HBV (ALT> 5xULN or >2 x baseline and HBV DNA >20,000 IU/ml) were randomized into tenofovir group (300mg/day) and telbivudine group (600mg/day) along with standard medical treatment. Clinical and laboratory parameters were evaluated at baseline, day-7, day-14, day-30 and day-90. HBV DNA was evaluated at baseline and after three months of therapy. Primary end point was survival or death at three months. Secondary end point was improvement of liver function assessed by Child-Turcotte Pugh score and MELD score at three months. Results: 30 patients were enrolled in the study and 15 of them received tenofovir and 15 patients received telbivudine. Most of the baseline parameters showed no difference except serum AST and serum creatinine level that showed statistically significant difference between two groups. After antiviral therapy both groups showed significant clinical improvement along with CTP and MELD scores. However statistically significant improvement between tenofovir and telbivudine groups was only seen with MELD score. Survival rate was 80% in tenofovir group and 60% in telbivudine group, but this was not statistically significant. Low serum albumin at baseline was predictor of mortality. Conclusion: In patients of ACLF-B, antiviral therapy with both tenofovir and telbivudine improve liver function, but there is no statistically significant difference in survival between tenofovir and telbivudine.

With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.

Prosaposin (PSAP), a highly conserved glycoprotein, is a precursor of saposins A–D. Accumulating evidence suggests that PSAP is a neurotrophic factor, as well as a regulator of lysosomal enzymes. Recently, the orphan G-protein-coupled receptors GPR37 and GPR37L1 were recognized as PSAP receptors, but their functions have not yet been clarified. In this study, we examined the distribution of PSAP and its receptors in the dorsal root ganglion (DRG) during development using specific antibodies, and showed that PSAP accumulates primarily in lysosomes and is dispersed throughout the cytoplasm of satellite cells. Later, PSAP colocalized with two receptors in satellite cells, and formed a characteristic ring shape approximately 8 weeks after birth, during a period of rapid DRG development. This ring shape, which was only observed around larger neurons, is evidence that several satellite cells are synchronously activated. We found that sortilin, a transporter of a wide variety of intracellular proteins containing PSAP, is strongly localized to the inner side of satellite cells, which contact the neuronal surface. These findings suggest that PSAP and GPR37/GPR37L1 play a role in activating both satellite and nerve cells.

Prosaposin (PSAP), a highly conserved glycoprotein, is a precursor of saposins A-D. Accumulating evidence suggests that PSAP is a neurotrophic factor, as well as a regulator of lysosomal enzymes. Recently, the orphan G-protein-coupled receptors GPR37 and GPR37L1 were recognized as PSAP receptors, but their functions have not yet been clarified. In this study, we examined the distribution of PSAP and its receptors in the dorsal root ganglion (DRG) during development using specific antibodies, and showed that PSAP accumulates primarily in lysosomes and is dispersed throughout the cytoplasm of satellite cells. Later, PSAP colocalized with two receptors in satellite cells, and formed a characteristic ring shape approximately 8 weeks after birth, during a period of rapid DRG development. This ring shape, which was only observed around larger neurons, is evidence that several satellite cells are synchronously activated. We found that sortilin, a transporter of a wide variety of intracellular proteins containing PSAP, is strongly localized to the inner side of satellite cells, which contact the neuronal surface. These findings suggest that PSAP and GPR37/GPR37L1 play a role in activating both satellite and nerve cells.

Spina bifida aperta (SBA), one of the most common congenital malformations, causes lifelong neurological complications, particularly in terms of motor dysfunction. Fetuses with SBA exhibit voluntary leg movements in utero and during early neonatal life, but these disappear within the first few weeks after birth. However, the pathophysiological sequence underlying such motor dysfunction remains unclear. Additionally, because important insights have yet to be obtained from human cases, an appropriate animal model is essential. Here, we investigated the neuropathological mechanisms of progression of SBA-like motor dysfunctions in a neural tube surgery-induced chicken model of SBA at different pathogenesis points ranging from embryonic to posthatch ages. We found that chicks with SBA-like features lose voluntary leg movements and subsequently exhibit lower-limb paralysis within the first 2 weeks after hatching, coinciding with the synaptic change-induced disruption of spinal motor networks at the site of the SBA lesion in the lumbosacral region. Such synaptic changes reduced the ratio of inhibitory-to-excitatory inputs to motor neurons and were associated with a drastic loss of γ-aminobutyric acid (GABA)ergic inputs and upregulation of the cholinergic activities of motor neurons. Furthermore, most of the neurons in ventral horns, which appeared to be suffering from excitotoxicity during the early postnatal days, underwent apoptosis. However, the triggers of cellular abnormalization and neurodegenerative signaling were evident in the middle- to late-gestational stages, probably attributable to the amniotic fluid-induced in ovo milieu. In conclusion, we found that early neonatal loss of neurons in the ventral horn of exposed spinal cord affords novel insights into the pathophysiology of SBA-like leg dysfunction.

Prosaposin (PS) is a secretory neurotrophic factor, as well as a regulator of lysosomal enzymes. We previously reported the up-regulation of PS and the possibility of its axonal transport by GABAergic interneurons after exocitotoxicity induced by kainic acid (KA), a glutamate analog. In the present study, we performed double immunostaining with PS and three calcium binding protein markers: parvalbumin (PV), calbindin, and calretinin, for the subpopulation of GABAergic interneurons, and clarified that the increased PS around the hippocampal pyramidal neurons after KA injection existed mainly in the axons of PV positive interneurons. Electron microscopy revealed PS containing vesicles in the PV positive axon. Double immunostaining with PS and secretogranin or synapsin suggested that PS is secreted with secretogranin from synapses. Based on the results from in situ hybridization with two alternative splicing forms of PS mRNA, the increase of PS in the interneurons was due to the increase of PS + 0 (mRNA without 9-base insertion) as in the choroid plexus, but not PS + 9 (mRNA with 9-base insertion). These results were similar to those from the choroid plexus, which secretes an intact form PS + 0 to the cerebrospinal fluid. Neurons, especially PV positive GABAergic interneurons, produce and secrete the intact form of PS around hippocampal pyramidal neurons to protect them against KA neurotoxicity.

Prosaposin (PSAP), a highly conserved glycoprotein, is a precursor of saposins A–D. Accumulating evidence suggests that PSAP is a neurotrophic factor that induces differentiation and prevents death in a variety of neuronal cells through the active region within the saposin C domain both in vivo and in vitro. Recently, GPR37 and GPR37L1 were recognized as PSAP receptors. In this study, we examined the alteration in expression of PSAP and its receptors in the cerebellum using rats injected with kainic acid (KA). The results show that PSAP was strongly expressed in the cytoplasm of Purkinje cells and interneurons in the molecular layer, and that PSAP expression in both types of neurons was markedly enhanced following KA treatment. Immunoblotting revealed that the expression of GPR37 was diminished significantly three days after KA injection compared with control rats; however, no changes were observed through immunostaining. No discernable changes were found in GPR37L1. These findings may help us to understand the role of PSAP and the GPR37 and GPR37L1 receptors in alleviating the neural damage caused by KA.

Neurotrophic factor prosaposin (PS) is a precursor for saposins A, B, C, and D, which are activators for specific sphingolipid hydrolases in lysosomes. Both saposins and PS are widely contained in various tissues. The brain, skeletal muscle, and heart cells predominantly contain unprocessed PS rather than saposins. PS and PS-derived peptides stimulate neuritogenesis and increase choline acetyltransferase activity in neuroblastoma cells and prevent programmed cell death in neurons. We previously detected increases in PS immunoactivity and its mRNA in the rat facial nucleus following facial nerve transection. PS mRNA expression increased not only in facial motoneurons, but also in microglia during facial nerve regeneration. In the present study, we examined the changes in immunoreactivity of the PS receptors GPR37 and GPR37L1 in the rat facial nucleus following facial nerve transection. Following facial nerve transection, many small Iba1- and glial fibrillary acidic protein (GFAP)-positive cells with strong GPR37L1 immunoreactivity, including microglia and astrocytes, were observed predominately on the operated side. These results indicate that GPR37 mainly works in neurons, whereas GPR37L1 is predominant in microglia or astrocytes, and suggest that increased PS in damaged neurons stimulates microglia or astrocytes via PS receptor GPR37L1 to produce neurotrophic factors for neuronal recovery.

The World Health Organization (WHO) South-East Asia Regional Office (SEARO) covers 11 countries with a combined population of about 2 billion people, making it the most populous of the six WHO regions. In 1992, the WHO advocated including the hepatitis B vaccine in the Expanded Program of Immunization (EPI) and vaccinating all infants and children three times within 1 year of birth (HepB3). Recently, the WHO advocate birth-dose hepatitis B vaccination (HepB-BD) as soon as possible after birth, preferably within 24 hours. In 2016, the SEARO endorsed a regional hepatitis B control goal with a target of hepatitis B surface antigen (HBsAg) seroprevalence of ≤1% among children aged ≥5 years by 2020. Of the 11 SEARO countries, four achieved this target on schedule. Out of these four countries, two countries (Bangladesh and Nepal) have not adopted HepB-BD in EPI program. On the other hand, the coverage of HepB3 is not satisfactory in some SEARO countries, including India which adopted HepB-BD but could not achieve the overall target of SEARO. Thus, it is a point of debate whether emphasis should be placed on proper implementation of HepB3 or whether a new agenda of HepB-BD should be incorporated in developing countries of SEARO. The article discusses strengthening and expanding the Hepatitis B vaccination program in SEARO countries with an emphasis on HepB and HepB-BD programs.

Growth hormone-releasing hormone (GHRH), a stimulator of growth hormone (GH) secretion, is known to have several physiological roles such as the regulation of feeding behavior in mammals. Recently, we have reported that central injection of chicken GHRH decreased food intake in chicks, however, its peripheral role on feeding behavior has not been clarified. The purpose of the present study was to investigate the effect of peripheral injection of GHRH on feeding behavior in chicks (Gallus gallus). Intraperitoneal (IP) injection of GHRH47 (1 nmol), full length form of chicken GHRH significantly decreased food intake in chicks although the injection of GHRH27 and GHRH27-NH2, short forms of chicken GHRH had no effect. The IP injection of GHRH47 did not induced any abnormal behavior, suggesting that GHRH47-induced anorexia might not be related to abnormal behavior such as sleeping, hyperactivity and convulsion. The anorexigenic effect of GHRH47 seemed not to be related to GH because IP injection of bovine GH did not affect feeding behavior in chicks. Collectively, these results suggest that peripheral GHRH is related to inhibit feeding behavior in chicks.

Growth hormone secretagogues (GHS), including ghrelin, are known to stimulate feeding behavior in mammals. In contrast, intracerebroventricular (ICV) injection of rat or chicken ghrelin, strongly inhibits food intake in chicks. The difference prompted us to compare the effect of growth hormone releasing peptide-6 (GHRP-6), one of synthetic GHSs on feeding behavior of chicks with that of ghrelin. Gastric motility stimulating action of GHRP-6 was also examined in vivo measuring retention of food in digestive tracts. ICV injection of GHRP-6 (0.38nmol-1.5nmol) dose-dependently inhibited food intake of neonatal chicks under both ad libitum and fasting conditions. The anorexic effect of GHRP-6 was attenuated by D-Lys3-GHRP-6 (GHS receptor antagonist) in a dose dependent manner. Central injection of GHS agonist and/or antagonist did not affect food retention in crop, proventriculus and gizzard. These results suggest that central injection of synthetic GHS, GHRP-6 inhibits feeding behavior as dose ghrelin without affecting gastrointestinal motility in layer chicks.