Interaction of Nucleoside Analogues with the Sodium–Nucleoside Transport System in Brush Border Membrane Vesicles from Human Kidney

The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na⁺-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na⁺-driven ³H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na⁺–uridine transport was determined. At a concentration of 100 µM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a K _i of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na⁺–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The K _i of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.     

Histamine turnover in the brain of morphine-dependent mice

Summary The turnover of brain histamine was examined in mice implanted subcutaneously with a morphine pellet (50 mg free base). The numbers of naloxone-precipitated jumpings and body shakes were maximum 2 and 3 days after implantation, respectively. The brain tele-methylhistamine level significantly increased (50% to 115%) during 12 h3 days after implantation of a morphine pellet, whereas the histamine level remained unchanged. The accumulation of tele-methylhistamine by pargyline treatment was significantly enhanced when pargyline was administered 12 h after implantation, suggesting an enhancement of histamine turnover. However, a similar degree of the tele-methylhistamine accumulation was induced by pargyline during 1–5 days after implantation, as compared with the accumulation in the control mice implanted with a placebo pellet. In mice undergoing morphine withdrawal by either the removal of morphine pellet or the treatment with naloxone 3 days after implantation, the degree of the pargyline-induced telemethylhistamine accumulation or the (S)--fluoromethylhistidine (-FMH)-induced histamine decrease was similar to that observed in the placebo pellet-control mice. The numbers of naloxone-precipitated jumpings and body shakes occurring in mice 3 days after implantation were not significantly affected by any of l-histidine, -FMH or metoprine. These results suggest that turnover of histamine in the brain is enhanced by acute morphine treatment and returns to the normal rate in the stage of chronic treatment and remains unchanged during the state of withdrawal. Send offprint requests to K. Saeki     

The death drive exemplified in a case of alcohol dependence

• ? When Freud first advanced the death drive it was considered a highly controversial theoretical idea. However, with the passage of time it has been slowly gaining support in certain psychoanalytical quarters.
• ? This paper aims to demonstrate the clinical usefulness of this theory in accordance with the Freudian and Kleinian model.
• ? Although the case history to be discussed is a severe case of alcohol dependence which had, previously, been unresponsive to treatment, many other maladies, both mental and physical, can be better understood in the context of the death drive being the principal motivating factor.

     

尼古丁依赖的功能影像学研究进展

在过去10年中,随着功能脑影像学技术在物质滥用领域的发展,越来越多的研究者运用这些技术以探讨尼古丁成瘾的神经生物学机制。本文主要总结了尼古丁急、慢性暴露下对脑功能影响的神经脑影像学研究进展,证实了尼古丁依赖与中脑边缘犒赏系统、调节注意、记忆、运动以及联想相关脑环路之间的相关性。这些研究发现将为揭示尼古丁依赖的神经生物学机制提供更多的证据支持,进一步促进今后戒烟治疗的发展。     

门诊精神病人治疗依从性及其影响因素分析

目的 了解门诊精神病人治疗依从性及其影响因素,探讨提高治疗依从性的对策.方法 对500例门诊精神病人进行有关治疗依从性方面的调查,分析影响治疗依从性的有关因素及所采取的对策等.结果 治疗依从性差多发生于疾病的复发期(64.9%)和进展期(63.1%),平均持续8.7天.依从性差的原因主要为:病情较严重、无自知力、药物副作用以及缺乏经济和情感上的支持.所采取的对策为:应用长效针剂、调整剂量、加强监管等.结论 应加强用药指导、健康教育和心理辅导,以提高精神病人的用药依从性.     

Evidence for effector independent and dependent representations and their differential time course of acquisition during motor sequence learning

To investigate the representation of motor sequence, we tested transfer effects in a motor sequence learning paradigm. We hypothesize that there are two sequence representations, effector independent and dependent. Further, we postulate that the effector independent representation is in visual/spatial coordinates, that the effector dependent representation is in motor coordinates, and that their time courses of acquisition during learning are different. Twelve subjects were tested in a modified 2x10 task. Subjects learned to press two keys (called a set) successively on a keypad in response to two lighted squares on a 3x3 display. The complete sequence to be learned was composed of ten such sets, called a hyperset. Training was given in the normal condition and sequence recall was assessed in the early, intermediate, and late stages in three conditions, normal, visual, and motor. In the visual condition, finger-keypad mapping was rotated 90 degrees while the keypad-display mapping was kept identical to normal. In the motor condition, the keypad-display mapping was also rotated 90 degrees, resulting in an identical finger-display mapping as in normal. Subjects formed two groups with each group using a different normal condition. One group learned the sequence in a standard keypad-hand setting and subsequently recalled the sequence using a rotated keypad-hand setting in the test conditions. The second group learned the sequence with a rotated keypad-hand setting and subsequently recalled the sequence with a standard keypad-hand setting in the test conditions. Response time (RT) and sequencing errors during recall were recorded. Although subjects committed more sequencing errors in both testing conditions, visual and motor, as compared to the normal condition, the errors were below chance level. Sequencing errors did not differ significantly between visual and motor conditions. Further, the sequence recall accuracy was over 70% even by the early stage when the subjects performed the sequence for the first time with the altered conditions, visual and motor. There were parallel improvements thereafter in all the conditions. These results of positive transfer of sequence knowledge across conditions that use dissimilar finger movements point to an effector independent sequence representation, possibly in visual/spatial coordinates. Initially the RTs were similar in the visual and the motor conditions, but with training RTs in the motor condition became significantly shorter than in the visual condition, as revealed by significant interaction for the testing stage and condition term in the repeated measures ANOVA. Moreover, using RTs for single key pressing in the three conditions as baseline indices, it was again observed that RTs in the visual and motor conditions were not significantly different in the early stage, but motor RTs became significantly shorter by the late testing stage. These results support the hypothesis that the motor condition benefits more than the visual because it uses identical effector movements to the normal condition. Further, these results argue for the existence of effector dependent sequence representation, in motor coordinates, which is acquired relatively slowly. The difference in the time course of learning of these two representations may account for the differential involvement of brain areas in early and late learning phases found in lesion and imaging studies.     

Active Ca2+ reabsorption in the proximal tubule of the rat kidney

Summary Using the stop flow microperfusion technique with simultaneous capillary perfusion the rate of active Ca²⁺ reabsorption was evaluated by measuring the static head electrochemical potential difference as well as the permeability of the tubular wall for Ca²⁺ ions. Under control conditions the active Ca²⁺ transport was calculated to be 3.35×10^–13 mol/cm·s. It declined toward zero if the ambient Na⁺ was replaced by choline or lithium. Parallel experiments in the golden hamster showed that active Ca²⁺ transport, vanished completely if active Na⁺ transport was blocked by ouabain (1 mM). These data indicate that the active Ca²⁺ reabsorption from the proximal tubule depends on the active reabsorption of Na²⁺ presumably via a Na⁺–Ca²⁺ countertransport at the contraluminal cell membrane. The static head electrochemical potential difference of Ca²⁺ is the same in late and early proximal tubules. It is also not affected by the presence of acetazolamide (10^–4 M) by the absence of bicarbonate or glycodiazine buffer or by the absence or presence of phosphate (2 mM).     

Superfluousness of motor innervation for the formation of muscle spindles in neonatal rats

Summary Muscle spindles form de novo in reinnervated muscles of neonatal rats treated with nerve growth factor. Whether the spindles can also form in muscle reinnervated only by afferents was investigated by removing the lumbosacral segment of the spinal cord immediately after crushing the nerve to the medial gastrocnemius muscle at birth, and administering nerve growth factor for 10 days afterwards. As predicted, the medial gastrocnemius muscles were reinnervated by afferents, but not efferents. No motor endplates were visible on any muscle fibers, and extrafusal fibers were atrophied. The reinnervated muscles contained spindle-like encapsulations of one to four fibers at 5, 7, 9 and 30 days after the nerve crush. The number of spindles as well as encapsulated fibers exceeded that of normal medial gastrocnemius muscles. The encapsulated fibers resembled typical intrafusal fibers. They had normal sensory-muscle contacts, but no motor endings. The fibers displayed equatorial clusters of myonuclei and expressed the spindle-specific slow-tonic myosin heavy chain isoform at postnatal day 30. Thus, efferents are not essential for the formation and differentiation of muscle spindles in reinnervated muscles of neonatal rats.