Acute hepatitis B caused by a vaccine-escape HBV strain in vaccinated subject: Sequence analysis and therapeutic strategy

HBV vaccine contains the ‘a’ determinant region, the major immune-target of antibodies (anti-HBs). Failure of immunization may be caused by vaccine-induced or spontaneous ‘a’ determinant surface gene mutants. Here, we evaluate the possible lack of protection by HBV vaccine, describing the case of an acute hepatitis B diagnosed in a 55-year-old Caucasian male unpaid blood donor, vaccinated against HBV. Sequencing data for preS–S region revealed multiple point mutations. Of all the substitutions found, Q129H, located in the “a” determinant region of HBsAg, can alter antigenicity, leading to mutants. This mutant may cause vaccine failure especially when associated with high viremia of infecting source.     

The mechanism of action of α2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

The precise mechanism of action of α₂ adrenoceptor blockers is not known, although in principle they have two main effects: (i) they stimulate the norepinephrinergic system by inhibiting the negative feed back of norepinephrine release (presynaptic effect) and (ii) they inhibit the effects of norepinephrine on postsynaptic α₂ adrenoceptors. We postulate that if the presynaptic actions of the antagonists prevail, the enhanced norepinephrine release leads to an activation of postsynaptic α₁ or β adrenoceptors. In this case the effects of α₂ adrenoceptor blockers can be reversed by antagonists acting on the latter two adrenoceptors, since postsynaptic α₂ adrenoceptors are also blocked. If the postsynaptic blockade of α₂ adrenoceptors is the main cause of effects, than the blockade of α₁ or β adrenoceptors should not reverse the action of α₂ blockers. The α₂ blocker idazoxan (dose 0.5–5 mg/kg) increased locomotor activity in an open field, an effect that was abolished by both α₁ and β receptor blockers (prazosin and propranolol, respectively). Escape responses in a shuttle box were strongly suppressed by idazoxan (0.5–2 mg/kg). However, this effect was not changed by concomitant α₁ or β receptor blockade. These results suggest that the mechanism of action of α₂ adrenoceptor blockers depends on which effects are studied. Exploration seems to be affected by a presynaptic mechanism as neurons bearing postsynaptic α₁ or β adrenoceptors are involved in the control of this behavior, while escape reactions appear to be affected by the postsynaptic blockade of α₂ adrenoceptors (i.e. neurons bearing postsynaptic α₂ adrenoceptors are involved in its control). Thus, there is no generalized mechanism of action for α₂ adrenoceptor blockers; their precise mode of action should be investigated in each particular case. Received: 15 November 1996 /Final version: 5 June 1997     

Effect of high doses of naloxone on shuttle avoidance acquisition in rats

Administration of high doses of naloxone intraperitoneally (2.5-10.0 mg/kg) resulted in a dose-related impairment of avoidance response acquisition in a shuttle avoidance paradigm in rats. Naloxone in this dose range produced a significant decrease in the number of intertrial responses but did not result in a significant dose-response. Escape latencies were not affected by naloxone administration at any dose tested. The effect of naloxone on activity and nociception are implicated as possible causes of the observed behavior. The results are discussed as behavioral evidence supporting theories postulating multiple opiate receptors.     

Prolonged and ubiquitous inhibition by interferon γ of bone resorption induced by parathyroid hormone-related protein, 1,25-dihydroxyvitamin D3, and interleukin 1 in fetal mouse forearm bones

Summary To investigate the mechanism of the inhibitory effects of interferon-γ (IFN-γ) on bone resorption, the effects of murine IFN-γ on⁴⁵Ca release from prelabeled fetal mouse forearm bones were investigated. Murine IFN-γ usually did not affect basal⁴⁵Ca release but almost completely and equipotently inhibited bone resorption induced by PTH(1-34), PTH-rP(1-34), 1,25(OH)₂D₃, and interleukin 1 (IL-1). The half-maximal concentration for inhibition of bone resorption induced by IL-1α was 25.8±14.6 U/ml (mean±SD for 13 experiments), which is not different from those for PTH, PTH-rP, and 1,25(OH)₂D₃. There was no correlation between prostaglandin E₂ concentration in the conditioned medium and⁴⁵Ca release from the IFN-γ-treated forearm bones. The inhibitory effect of IFN-γ on bone resorption induced by PTH-rP (1-34) or IL-1α continued during 6 days of culture, whereas that of calcitonin disappeared after 2 days of culture. These findings suggest that IFN-γ nonpreferentially inhibits bone resorption induced by various bone-resorbing factors in fetal mouse forearm bones via a PGE₂-independent mechanism. As no escape phenomenon developed in IFN-γ-treated bones, the cytokine may be potentially useful for treatment of certain patients with malignancy-associated hypercalcemia.     

Effects of bromocriptine in developing rat pups after 6-hydroxydopamine

The effects of low (0.5 mg/kg) and high (2.0 mg/kg) doses of bromocriptine (BCR) on activity and escape performance were examined during the first month of postnatal life in normal developing rat pups and littermates treated at 5 days of age with a combination of desmethylimipramine and 6-hydroxydopamine (6-OHDA). Such a procedure resulted in significant reductions in brain dopamine to concentrations 10-20% of vehicle controls while norepinephrine was unaffected. BCR increased general motor activity in vehicle pups at 13 and 19 days but had little effect on more mature animals. Pups who had not received BCR exhibited a decline in activity over the hour long observation period (habituation of activity) but this decline was abolished by both low (0.5 mg/kg) and high (2.0 mg/kg) doses of the agent. Stereotyped activity, particularly at 19 days was increased by BCR in 6-OHDA pups but not in vehicle animals, an effect suggesting denervation supersensitivity. Head dips in a hole box at 30 days of age were not influenced by BCR in vehicle pups but significantly reduced by BCR in 6-OHDA pups, suggesting that BCR might be acting to stimulate inhibitory dopaminergic mechanisms. Escape learning in a T-maze at 20 days and shuttle box at 28 days was disrupted by high doses of BCR in vehicle pups and both doses of BCR in 6-OHDA animals. The similarity with the behaviors observed in the clinical syndrome of attention deficit disorder with hyperactivity prompted a number of investigative groups including our own to suggest that the 6-OHDA model might serve as a useful and convenient paradigm to evaluate pharmacological agents that offer potential in the treatment of this most common disorder. From this perspective we would predict that BCR would have little clinical utility since it both failed to attenuate 6-OHDA induced hyperactivity and tended to disrupt performance in an avoidance learning task.     

Sex differences in fighting and defense induced in rats by shock and dextro-amphetamine during morphine abstinence

Male and female rats were injected with morphine while a control group received water injections. Four days following the final morphine injection, the animals received d-amphetamine and then were tested for their reaction to a stuffed leather glove. Drugged animals, while not showing a higher incidence of attack, did show increased escape tendencies when compared to controls. Both drugged and control animals were then shocked in the presence of either a same or different sexed conspecific. Nine measures of aggressive behavior were recorded from the pairs. Factor analysis of the nine intercorrelated measures produced two orthogonal aggressive factors — one indicative of defensive-threat behavior and one relating to actual fighting. Male-male pairs under morphine abstinence plus d-amphetamine scored significantly higher than the other groups on the fighting factor while drugged male-female pairs scored significantly higher on the defensive-threat factor. Although the fighting exhibited in this study was essentially restricted to male pairs under the drugged condition, evidence is presented suggesting that the agonistic behavior observed is not the species typical intermale aggression.     

Neoplasms escape selective COX-2 inhibition in an animal model of breast cancer

Background  Cyclo-oxygenase-2 (COX-2) is up-regulated in malignant tumours rendering it an attractive target for cancer therapeutics. However, whether long-term antagonism maintains its initial efficacy on established tumours is unclear. Methods  4T1 cells were injected into the mammary fat pad of BALB/c mice (n = 8). Once tumour deposits were established, animals were randomized into two equal groups to receive either a selective COX-2 inhibitor (SC-236) or a drug vehicle. Further animals similarly treated (n = 7) were studied in diuresis cages allowing urine capture and analysis by mass spectrometry to determine Prostaglandin F-1 levels (PGF-1). In addition, both wild-type receiving SC-236 and COX-2 knockout mice receiving either SC 236 or vehicle were subjected to the same studies to determine whether tumour-derived or host-derived (stromal) COX-2 was the critical element. Finally, BALB/c mice with 4T1 tumours (n = 7) were treated with a combination of COX-2 and lipoxygenase (LOX) inhibition to attenuate this escape phenomenon. Results  While selective COX-2 inhibition initially retarded tumour growth, a rapid increase in tumour growth rate occurred later (day 9). This escape phenomenon correlated with an increase in urinary PGF-1 levels. An identical trend was also observed whether COX-2 knockout mice received SC-236 or not, suggesting that this effect is due to increased tumour-derived COX-2 production rather than recovery of host COX-2 functional capacity. Finally, dual inhibition of COX and LOX pathways attenuated this escape process. Conclusion  The anti-neoplastic effects of selective COX-2 inhibition may not be sustained as tumours demonstrate an escape capacity. However, this phenomenon maybe attenuated by a combination of COX/LOX inhibitors.     

模拟3～30 m快速上浮脱险潜艇艇员肾动脉血流动力学的变化

目的:评价快速上浮脱险后潜艇艇员肾动脉血流动力学的变化。方法:应用多普勒超声对模拟3～30 m快速上浮脱险试验的艇员进行肾动脉血流动力学的监测。结果:3、10、30 m训练深度,双肾动脉阻力指数(RI)、搏动指数(PI)均在正常范围,并随着训练深度的加大变化无统计学意义。结论:浅深度快速上浮脱险对肾动脉血流动力学无显著影响,本次试验的训练方法及保障是安全有效的。