Hepatitis B surface antigen escape mutations: Indications for initiation of antiviral therapy revisited

Approximately 240 million people are chronically infected with hepatitis B. The implementation of rigorous vaccination programs has led to an overall decrease in the prevalence of this disease worldwide but this may also have led to emergence of viral mutations that can escape the protection of hepatitis B surface antibody. As this phenomenon is increasingly recognized, concern for transmission to vaccinated individuals has also been raised. Herein, we describe two cases where the suspected presence of a hepatitis B surface antigen escape mutation impacted the decision to initiate early antiviral therapy, as well as provide a brief review of these mutations. Our findings described here suggest that a lower threshold for initiating therapy in these individuals should be considered in order to reduce the risk of transmission, as vaccination does not provide protection.     

CD155在肿瘤中的研究进展

CD155（PVR/Necl-5）是一种细胞黏附分子,在肿瘤进展中发挥重要作用。CD155通过调节肿瘤相关信号通路,影响细胞增殖、迁移侵袭及黏附;或与免疫细胞上的DNAX辅助分子-1、T细胞免疫球蛋白和ITIM结构域和CD96相互作用,影响T细胞及自然杀伤细胞功能。在多种类型肿瘤细胞上均检测到CD155表达上调,且与患...     

Escaping aversive exposure

This research examined human defensive reactivity when exposure to an aversive event could be escaped but not entirely avoided. Prolonged visual cues indicated whether exposure to an upcoming aversive (i.e., disgusting) picture could be terminated after onset (escaped) or not, or that a neutral go signal would appear. Acoustically elicited startle reflexes were measured during each cue interval, as were cardiac and skin conductance activity. Early in the cuing interval, startle reflexes were potentiated during both escape and inescapable exposure trials, compared to the simple motor context. Later in the interval, reflexes remained potentiated for both escapable and inescapable trials, with potentiation further enhanced when aversive exposure could not be escaped compared to when exposure could be escaped. Heart rate deceleration in the cuing interval indicated increased vigilance when preparing any (escape or neutral) action, whereas skin conductance responding indicated enhanced sympathetic action mobilization particularly in an escape context. These data suggest that startle reflexes engaged in an escape context reflect both motor‐related response inhibition and aversive potentiation, and they indicate that defensive motivation is engaged whenever aversive exposure is guaranteed, regardless of whether it can be escaped or not.     

Low immunogenic bio-nanocapsule based on hepatitis B virus escape mutants

Bio-nanocapsules (BNCs) consisting of hepatitis B virus surface antigen (HBsAg) L proteins and phospholipids are used as efficient non-viral carriers for liver-specific delivery of genes and drugs. Considering the administration to HB vaccinees and HB patients, endogenous anti-HBsAg immunoglobulins (HBIGs) may reduce the delivery efficacy and prevent repetitive administration. Therefore, low immunogenic BNCs were generated by inserting two point mutations in the HBsAg L protein, which were found in HBV escape mutants. Escape mutant-type BNC (emBNC) showed 50% lower HBIG binding capacity than that of parental BNC (wtBNC). It induced HBIG production to a lesser extent than that associated with wtBNC in BALB/c mice. The emBNC could accumulate into human hepatocyte-derived tumor in mice pre-treated with HBIGs. The complex of emBNC and cationic liposomes could deliver plasmid DNA to HepG2 cells efficiently in the presence of HBIGs. Thus, emBNC could evade HBIG-neutralizing antibodies, expanding the clinical utility of BNC-based nanomedicine.     

The involvement of endogenous opiate systems in learned helplessness and stress-induced analgesia

The participation of endogenous opiate systems in the induction and expression of learned helplessness (LH) and stress-induced analgesia (SIA) was investigated in rats exposed to escapable and inescapable footshock. Following an initial footshock, analgesia was observed only in those animals that could not control their stress exposure and this SIA was prevented by the administration of naloxone. Analgesia was no longer evident in this inescapable group after 48 h. However, exposure to a shuttlebox escape task at this time reinstated the SIA but did not produce SIA in animals previously exposed to escapable footshock. Shuttlebox escape deficits indicative of LH were also exhibited by animals that received an inescapable footshock stress 48 h prior to testing. The analgesia and LH observed in the inescapable group were not affected by the administration of naloxone (3 mg/kg, IP) 10 min before shuttlebox exposure but were prevented when the same dose of naloxone was given before the initial stress. Thus, endogenous opiates clearly participate in the initial induction of LH and SIA and, although the degree of endogenous opiate involvement in the subsequent expression of these behaviors is unclear, it seems evident that their expression can occur in the presence of opiate antagonism and may therefore require the participation of additional transmitter systems.     

Enhancement of pseudoconditioning and retardation of escape by low doses of ethanol

Independent groups of mature Wistar rats were injected intraperitoneally with 0.9% NaCl solution or 0.5 g/kg, 1 g/kg or 2 g/kg ethanol prepared from a 30% ethanol solution in 0.9% NaCl. Thirty min later each animal was placed in a two compartment shuttlebox and given 25 trials during which footshock was presented every 60 sec and tones of 8 sec duration were randomly programed. Shock-escape latencies and frequencies of intercompartmental (pseudoconditioned) responses to the tone were measured. The results showed that 1 g/kg and 2 g/kg ethanol significantly retarded escape performance but 2 g/kg ethanol significantly enhanced pseudoconditioning. These findings have implications for the design of experiments concerned with the effects of drugs on learning processes, and for theories of the effects of ethanol on behavior.     

Effect of inescapable shock on subsequent escape performance: Catecholaminergic and cholinergic mediation of response initiation and maintenance

Following exposure to inescapable shock, subsequent escape performance is disrupted if the task is one in which animals receive forced exposure to shock for several seconds before escape is possible. The extent of the deficit is directly related to the severity of the initial stress and the duration of escape delay used during test. Treatment with a tyrosine hydroxylase inhibitor, -methyl-p-tyrosine (-MpT), a dopamine--hydroxylase inhibitor, FLA-63, or dopamine antagonists, haloperidol, and pimozide, mimicked the effects of inescapable shock in the different escape paradigms. The effects of haloperidol were antagonized by treatment with scopolamine. As observed in the case of inescapable shock, prior escape training abated the disruptive effects of the drug treatments. Finally, decreasing or blocking catecholamine activity or increasing cholinergic activity exacerbated the effect of a moderate amount of inescapable shock on subsequent escape performance. These treatments also induced reductions in shock-elicited activity. Conversely, treatment with a catecholamine stimulant, l-dopa, or a cholinergic blocker, scopolamine, anatagonized the reduction in shock-elicited activity and the escape deficits engendered by prior inescapable shock. It was hypothesized that both DA and NE, as well as ACh, are involved in the escape deficit observed after inescapable shock, and that these transmitters mediate the interference by their influence on response initiation and maintenance, rather than on associative or cognitive processes.     

Relation of rat brain acetylcholine levels to duration of self-stimulation and escape behavior

Total brain acetylcholine (ACh) was assayed in groups of animals after various periods of operant responding maintained by electrical stimulation of the lateral posterior hypothalamus or of escape behavior induced by electrical stimulation of the midbrain tegmentum. Different groups of trained rats were placed in identical Skinner boxes for periods of 1 to 24 hr. The following groups were studied: controls, self-stimulators receiving electrical stimulation, escapers from brain stimulation or peripherally applied aversive stimulation, self-stimulators not receiving electrical stimulation prior to decapitation, tubocurarine-paralyzed respired rats with electrodes in the posterior-lateral hypothalamus not receiving stimulation, and a group of tubocurarine-paralyzed, respired rats receiving electrical stimulation automatically. It was found that brain stimulation decreased total brain ACh, regardless of whether the stimulation was positive, as during self-stimulation behavior, or negative, as during escape behavior. Animals that received positive stimulation while being paralyzed showed similar decreases in total brain ACh, but the change in ACh was smaller. No changes occurred in animals that were paralyzed that received no electrical stimulation. It is concluded that brain usage produced by electrical stimulation of discrete functional pathways causes a reduction of total ACh, but this is unrelated to the specific motivational properties of the electrical stimuli.     

Effects of d-amphetamine and ethanol on responding of squirrel monkeys maintained under fixed-ratio schedules of food presentation and stimulus-shock termination.

Effects of d-amphetamine and ethanol were assessed on comparable behaviors maintained under fixed-ratio schedules of either food presentation or termination of electric shock and an accompanying visual stimulus. Ethanol affected the behaviors similarly in all important aspects; d-amphetamine increased rates of responding maintained by stimulus-shock termination at doses that did not affect rates of food-maintained responding. The increases in responding maintained by stimulus-shock termination were not solely due to decreases in the pause prior to the initiation of responding.     

Effects of hypothalamic lesions on central gray stimulation induced escape behavior and on withdrawal reactions in the rat

The effects of unilateral--medial or lateral--hypothalamic lesions were studied with regard to both switch-off (i.e., escape) responding induced by central gray (CG) stimulation and responsiveness of the same animals to peripherally-applied electrical or thermal stimulation. Medial hypothalamic (MH) lesions were found to reduce--but not abolish--the efficiency of CG stimulations applied on the side of the MH lesion, while the efficiency of contralaterally applied CG stimulations remained unchanged. Furthermore, such lesions enhanced the responsiveness to peripheral nociceptive stimuli on whatever body side they were applied. Lateral hypothalamic lesions were found to only slightly--or not at all--affect the efficiency of CG stimulations, while they enhanced the responsiveness to peripheral nociceptive stimuli on either side of the body. These results suggest that the hypothalamus does not exert a univocal control over both centrally induced escape behavior and peripherally induced withdrawal reactions.