Effect of psychotomimetics and some putative anxiolytics on stress-induced hyperthermia

Summary Stress-induced hyperthermia (SIH), which is seen in the last mice removed from the cage, is a novel animal model sensitive to anxiolytic drugs. SIH is antagonized by CL 218872 (25 and 50 mg/kg, os), by tracazolate (5 and 7.5 mg/kg, ip) and by 2-AP-5 (50 and 100 mg/kg, ip). At higher dose, CL 218872 (100 mg/kg, os) and tracazolate (12.5 mg/kg, ip) lose their activity.PK 9084 (5–40 mg/kg, ip) and CGS 9896 (2–20 mg/kg, both ip and os) were also ineffective in preventing SIH. The anti-hyperthermic effect of CL 218872 (25 mg/kg) and tracazolate (7.5 mg/kg) was blocked by the benzodiazepine antagonist Ro 15–1788 (15 mg/kg). CGS 9896 (10 mg/kg, os) also reversed the effect of CL 218872 (25 mg/kg) on SIH.Differently from anxiolytics, MK-801 (0.5–1 mg/kg, os), PCP (2.5 mg/kg, ip) and d-amphetamine (10 mg/kg, ip) evoked hyperthermia in the first set of mice and prevented a further stress-induced rise of body temperature in the last set of mice.     

Patch clamp studies on the kinetics and selectivity of N-methyl-d-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan)

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-d-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg²⁺ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2–33 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC₅₀ of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1–100 μM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1–100 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC₅₀ of 12.9 ± 1.5 μM.     

艾滋病合并卡氏肺囊虫肺炎影像表现分析

目的 :探讨艾滋病病人卡氏肺囊虫肺炎 (PCP)的X线及CT表现。方法 :收集临床确诊的艾滋病病人卡氏肺囊虫肺炎胸部X线及CT照片 6例。分析其病变影像学表现及治疗后的影像观察。结果 :本病的典型影像表现 :双侧肺门周旁及双侧中下肺野弥漫性网格状影、磨玻璃状改变、弥漫性小结节影、斑片影 ;少见的合并表现 :肺气囊肿、胸水、胸部淋巴结肿大、大叶性实变。结论 :本病影像表现有一定特征性 ,影像检查对本病的临床诊断及观察治疗效果有显著的价值。     

Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys

  Rationale: Progressive ratio (PR) schedules have become well accepted for testing the reinforcing effectiveness of drugs. This study extends the methods to concurrent PR schedules with different concentrations of orally delivered phencyclidine (PCP). Objective: The sensitivity of the procedure is tested by presenting different PCP concentrations with independently-operating PR schedules. Method: PCP self-administration was investigated in seven rhesus monkeys. Six different PCP concentrations (0.03–1.0 mg/ml) and water were randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip-contact responses on solenoid-operated drinking spouts; whereby, the response requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096) after each successful completion of a previous FR and subsequent liquid delivery. Monkeys self administered PCP during daily 3-h sessions, and each pair of concentrations was held constant until behavior had stabilized for at least 4 days. Results: The higher of the two PCP concentrations always maintained greater responding, PR break point (BP), or the last ratio completed, and liquid deliveries than did the lower concentration. However, the monkeys did not exclusively respond on the drinking spout that yielded the higher drug concentration. When examined across all drug pairings, the percentage of total available deliveries of the higher concentration was significantly greater than those of the lower concentration. The monkeys maximized the amount (mg) consumed for the response output. Responding, BPs and liquid deliveries maintained by 0.12 and 0.25 mg/ml PCP were significantly greater than other PCP concentrations; however, drug intake (mg) increased directly with PCP concentration. Conclusion: These results indicate that concurrent PR schedules using oral drug self-administration and a concurrent choice paradigm reliably provide an estimation of relative reinforcing strength, and behavior maintained by these schedules is sensitive to small changes in PCP concentration. Received: 18 September 1998 / Final version: 28 December 1998     

Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo

Previous results in experimental systems have suggested that hydroxylated PCBs may decrease thyroid hormone levels through associative interaction with transthyretin. In the present paper it was investigated whether this property was also shared by various industrial chemicals, mainly pesticides. In total, 65 compounds from 12 chemical groups were analyzed for direct interference with the T4 binding site of transthyretin using a competitive binding assay. Sixty per cent of the compounds were competitive at a concentration level of 100 M. Relatively strong interactions were observed by several chlorophenols, chlorophenoxy acids and nitrophenols, as well as by individual compounds such as hexachlorobenzene, dicofol, bromoxynil and tetrachlorohydroquinone. Examples from these chemical groups, e.g. pentachlorophenol, 2,4-dichlorophenoxybutyric acid, dinoseb and bromoxynil, also reduced plasma TT4 levels in rats. In addition, bromoxynil decreased plasma TT3 levels. The results suggest the existence of a number of halogenated industrial chemicals with a potential for lowering plasma thyroid hormone levels through interference with hormone transport carriers.     

Pneumocystis-carinii- Pneumonie bei HIV-infizierten Kindern Umfrage an deutschen Kinderkliniken*

Zusammenfassung Fragestellung: Retrospektive Auswertung der Erkrankungen HIV-infizierter Kinder (<18 Jahre) an einer Pneumocystis-carinii-Pneumonie. Erfa?t wurden Prophylaxesituation, Krankheitsverlauf und Prognose. Methode: Ein Fragebogen wurde an alle 16 p?diatrischen Zentren in Deutschland, die HIV-infizierte Kinder betreuen, verschickt und deskriptiv ausgewertet. Ergebnisse: Von Januar 1989 bis Dezember 1995 wurden aus 6 klinischen Zentren 21 Patienten mit Pneumocystis-carinii-Pneumonie mitgeteilt (1–5 Erkrankungen pro Jahr). In den übrigen 10 Zentren wurden in diesem Zeitraum keine Patienten mit Pneumocystis-carinii-Pneumonie behandelt. 17 Kinder erwarben die HIV-Infektion pr?- und perinatal, 4 Kinder durch Blut oder Blutprodukte. Das Alter der vertikal infizierten Kinder betrug im Median 5 Monate. 15/21 Kindern erhielten keine Pneumocystis-carinii-Prophylaxe. Davon wurden 10 Patienten zum Zeitpunkt der Diagnosestellung nicht durch die aktuell geltenden Prophylaxerichtlinien der Centers for disease control erfa?t, und bei 5 Kindern wurde die HIV-Exposition erst mit Diagnosestellung der Pneumocystis-carinii-Pneumonie bekannt. Die akute Letalit?t betrug 29%, die Letalit?t der beatmeten Kinder 71%. Bis Juni 1996 betrug die mittlere überlebenszeit aller Patienten 20,3±19,1 Monate. Die überlebenszeit der bereits im 1. Lebensjahr erkrankten Kinder war mit 14,8±18,4 Monaten deutlich, aber nicht signifikant kürzer als diejenige der sp?ter erkrankten Kinder (27,6±18,5 Monate). Die nach Kaplan-Meier gesch?tzte 1-Jahres-überlebenszeit betrug 66%. Schlu?folgerungen: Die Pneumocystis-carinii-Pneumonie bei HIV-infizierten Kindern ist in Deutschland eine seltene Erkrankung mit ernster Prognose. Obwohl eine effektive Prophylaxe zur Verfügung steht, treten immer wieder Pneumocystis-carinii-Pneumonien auf, insbesondere bei Kindern, deren HIV-Exposition nicht rechtzeitig erkannt wurde. Die in dieser Umfrage ermittelten überlebenszeiten sind im internationalen Vergleich eher günstig.      

保元汤加减对实验大鼠肺孢子虫作用的电镜观察

目的　探索中医药治疗卡氏肺孢子虫肺炎的途径。　方法　应用中药保元汤加减煎剂给实验大鼠灌胃 ,通过透射电镜观察其对实验大鼠肺内肺孢子虫的作用。　结果　实验组较对照组大鼠肺内肺孢子虫有明显改变。其中肺孢子虫胞浆内大量空泡形成 ;包囊壁明显破坏 ;虫体有溶解现象。　结论　保元汤加减煎剂 ,对实验大鼠体内的卡氏肺孢子虫具有抑制和杀灭作用。     

Rare LRP6 Variants Identified in Spina Bifida Patients

Several single‐nucleotide variants (SNVs) in low‐density lipoprotein receptor‐related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like Crooked tail and Ringleschwanz mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein mesoderm development and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant downregulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys, and p.Arg1574Leu) increased noncanonical Wnt/planar cell polarity (PCP) signaling in an Ap1‐luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTDs, whereas Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure.     

Modifiable Failures in the Colorectal Cancer Screening Process and Their Association With Risk of Death

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