Quantitative structure-activity relationships in MAO-inhibitory 2-phenylcyclopropylamines: Insights into the topography of MAO-A and MAO-B

Ten (E)-and (Z)-isomers of 2-phenylcyclopropylamine (PCA), 1-Me-PCA, 2-Me-PCA, N-Me-PCA, and N, N-diMe-PCA and fifteeno ⁻, m⁻, p⁻ isomers of (E)-PCA with substituents of Me, Cl, F, OMe, OH were synthesized in this laboratory and tested for the inhibition of rat brain mitochondrial MAO-A and MAO-B. The effects of substituents, their positions, and stereochemistry on the inhibition were assessed for the compounds with substituents at cyclopropyl and amino groups and QSAR analyses were performed using the potency data of ring-substituted compounds. The best correlated QSAR equations are as follows: pI₅₀=0.804 Π² Blo−1.069 Blm+0.334 Lp−1.709 HDp+7.897 (r=0.945, s=0.211, F=16.691, p=0.000) for the inhibition of MAO-A; pI₅₀=1.815 π-0.825 Π² R+0.900 Es²+0.869 Es³+0.796 Es⁴−0.992 HDp+0.562 HAo+3.893 (r=0.982, s=0.178, F=23.351, p=0.000) for the inhibition of MAO-B. Based on the potency difference between stereoisomers of cyclopropylamine-modified compounds and on QSAR results, it is proposed that the active sites of MAO-A are composed of one deep hydrophobic cavity near para position, two hydrophobic cavities interacting with Me group, a hydrophobic area accomodating phenyl and cyclopropyl backbone, steric boundaries, a hydrogen-acceptor site near para position, and an amino group binding site and that in addition to the same two hydrophobic cavities, hydrophobic area, steric boundaries, hydrogen-acceptor site, and amino group binding site, another steric boundary near para position and a hydrogen donating site near ortho position constitute active sites of MAO-B.     

股骨颈骨折几种闭合复位方法的评价(译文)

在股骨颈移位骨折的治疗中,试用了7种不同的闭合复位方法。其中Whitman's法在骨折床台上进行,正常肢体外展,患肢由屈曲牵引至完全伸直位后,维持牵引并外展到与对侧肢体相称位,单髋人字石膏外固定(1914年)。 Leadbetter's法也在骨折床台上进行。将患肢髋部屈曲90°,沿大腿轴线行手法牵引。同时股骨干稍内收,患肢缓慢行环形活动至外展、内旋位,患肢向下降至骨折床台面时,行跟掌试验以验证是否完全复位(1933年)。 Bozan's法利用骨折床台使双下肢维持在伸直位,大绷带放置在患肢髂嵴部位,小绷带放置在患肢腹股沟皱襞最高点处实施牵引。然后整个患肢极度内旋,在维持侧方牵引的同时,患肢外展并轻度过牵(1934年)。     

Multiple sclerosis: myelin basic protein induced mRNA expression of proinflammatory cytokines in mononuclear cells is suppressed by interferon-β 1b in vitro

Beta-interferon (IFN-β) is a promising treatment in multiple sclerosis (MS), reducing the exacerbation rate and MRI lesion burden, as well as the disease progression in relapsing-remitting MS. IFN-β was originally defined by its antiviral effects, but the interest has recently been focused on its immunomodulatory properties. Myelin basic protein (MBP) is one of several autoantigens considered to be the target for autoaggressive immune responses, which eventually might lead to the development of MS. To study in-vitro effects of IFN-β1b on MBP induced cytokine expression, mRNA for the Th1 cytokines IFN-γ and TNF-α, the Th2 related IL-4 and IL-6, the cytolytic perforin and the immune response downregulating TGF-β was measured with in situ hybridization after culture of blood mononuclear cells (MNC) in the presence and absence of MBP. Numbers of cells expressing IFN-γ, TNF-α, perforin and IL-4 mRNA were significantly suppressed after culture with 10 U/ml IFN-β1b. No such effect was seen on MBP induced IL-6 or TGF-β mRNA expression. These observations suggest that one of the major effects of IFN-β1b is the induction of a shift in the cytokine mRNA profile towards a more immunosuppressive pattern. In parallel in vitro tests, the control substance dexametasone (40 μg/ml) reduced the numbers of cells expressing mRNA for all cytokines under study with the exception of TGF-β, to an extent equal to or even more pronounced than IFN-β1b.     

Elevated extracellular potassium is associated with a reduced extracellular space in rat neural lobe in vitro

Summary Increased neural activity of neurosecretory cells is accompanied by large increases in extracellular K⁺. The possibility that elevations of this ion might involve fluid redistribution and thus affect the size of the extracellular space and the relationship between pituicytes and axons in the rat neural lobe was explored using rapid freezing and freeze-substitution. Neural lobes were incubated for 15 min before freezing either in a normal medium or one containing a 10 mM increase in KCl (high KCl), a 10 mM increase in KCl balanced by an equimolar reduction in NaCl (high KCl-low NaCl), or only a 10 mM reduction in NaCl (low NaCl). A quantitative assessment of the region of good fixation was made to determine the relative fractions occupied by axons, pituicytes and the extracellular space near the neurohaemal contact zone. In addition, the percentage of basal lamina contacted by pituicytes and axons was calculated, as was the degree of enclosure of axons by pituicytes.In neural lobes incubated in normal medium, the extracellular space accounted for approximately 30% of the cross-sectional area of the neuropil and could be divided into two domains: an extended perivascular space (28–29% of total area); and a narrow (approximately 24 nm; approximately 1% of total) space between closely apposed neurosecretory processes or between these processes and pituicytes. Pituicytes occupied almost 60% of the basal lamina at the neurohaemal contact zone, while axons occupied approximately 20%. Neural lobes incubated in either the high KCl solution, or in the high KCl-low NaCl solution, exhibited a significantly reduced extracellular space, to about 20% of the total area, or a reduction from controls of about one-third. The reduction was complemented by an increased area occupied by axons plus pituicytes. In the high KCl group, the contribution of the narrow spaces (22–24 nm) between apposed processes to the total extracellular space was greatly increased. The group exposed to low NaCl showed high variability in the size of extracellular space, and was thus not significantly different from any other group. No changes in any group were observed in the enclosure of axons by pituicytes, or in the relative amounts of axon and pituicyte apposition to the basal lamina.The subsequent buffering of K⁺ and other ions during periods of increased neuronal activity may be affected by changes in the extracellular space, thereby influencing stimulus-secretion coupling. A shrinkage of the extracellular space and the relative increase in the narrow spaces between processes initiated by elevated K⁺ could also alter the diffusion properties of the neural lobe.     

小剂量氯化汞对小鼠脂质过氧化物的影响

本观察小剂量１ｍｇ／ｋｇ）ＨｇＣｌ２对小鼠肝，脑组织中脂质过氧化物（ＬＰＯ）的影响，发现小剂量ＨｇＣｌ２可使肝组织中ＬＰＯ含量明显增高，与对照组比，差异有显性（Ｐ〈０．０２５），而脑组织中ＬＰＯ含量未见明显影响（Ｐ〉０．０５）。     

玻璃体腔内注气治疗黄斑裂孔视网膜脱离

采用玻璃体腔内注气治疗黄斑裂孔视网膜脱离４９例（５３只眼），视风膜复位４２只眼（７９．２％），其中术后视力增进２９只眼（６９％），讨论了注气的适应征和影响视网膜复位的因素。     

305例老年死亡病例医院感染回顾性调查

本文结果表明,305例老年死亡病例医院感染的发病率为33.8％。感染最多部位为肺部(66.9％),其次为尿路感染(19.4％)。高龄患者,侵袭性操作、多种抗生素联合应用,激素疗法等是诱发医院感染的危险因素。58.8％的病原菌为革兰氏阴性杆菌,37.2％为真菌。31株病原菌药敏结果显示耐药率为33.3％。本文指出合理应用抗生素是预防医院感染的重要措施之一。     

Ag—NOR计数在区分良恶性甲状腺病变中的意义

随机选择经长期随访证实的滤泡性甲状腺癌和腺瘤各10例,正常甲状腺组织5例作为对照。按Ploton的染色方法和Crocker推荐的计数方法分别计算三组每例各50个细胞的Ag-NOR嗜银颗粒平均数,再算出三组各自的AgNOR均数,经统计学检验三者有极显著性差异。可望成为甲状腺滤泡性肿瘤良恶鉴别的一项辅助指标。     

Statistical MUNE: A comparison of two methods of setting recording windows in healthy subjects and ALS patients

OBJECTIVE: To address the issue as to how best to perform statistical MUNE, we applied two different approaches and compared results in healthy subjects and ALS patients. METHODS: Twelve normal subjects (women 8, mean age 52years) and 11 ALS patients (women 4, mean age 54years) underwent two consecutive MUNE studies, which differed in terms of setting and modifying the recording window. These are referred to as the 'expansion' and 'narrowing' methods, respectively. Size-weighted average (Av) SMUP and MUNE values were obtained using the two methods, and compared in control and patient groups. RESULTS: Expansion method-derived Av SMUP sizes and MUNE values differed only slightly from those obtained using the narrowing method in healthy subjects, whereas the narrowing method resulted in significantly larger Av SMUP sizes and smaller MUNE values than the expansion method in ALS patients (Wilcoxon signed ranks test, p=0.003). The sizes of tested areas (mean+/-SD) were significantly larger for the narrowing method than the expansion method in both subject groups with much greater difference in ALS patients; 9.6+/-3.1% vs. 7.9+/-1.7% in healthy subjects and 16.1+/-5.1% vs. 11.2+/-3.0% in ALS patients (Student t-test, p<0.01). CONCLUSIONS: The present study shows, unlike that found in normal subjects, that the results of statistical MUNE in ALS patients are heavily dependent on the approach used to set and modify recording windows. SIGNIFICANCE: The expansion method using a 10%-sized window is likely to suffer from systemic errors due to the ceiling effect and the sampling of artifactually small motor units in ALS patients. The authors recommend that the narrowing method be considered as an alternative that avoids these problems.     

脉络膜黑色素瘤脱色素处理后Caspase-3的免疫组化研究

目的 观察凋亡基因Caspase-3在脉络膜黑色素瘤(choroidal melanoma)中的表达及分型与细胞凋亡的关系。方法 收集20例脉络膜黑色素瘤标本，对其进行Caspase-3免疫组织化学染色，观察表达情况及染色强度。结果 Caspase-3在脉络膜黑色素瘤有较好的表达，在梭形细胞型中5例／6例呈阳性表达，在混合型中6例／8例呈阳性表达，在上皮样瘤细胞型中3例／4例呈阳性表达，在坏死型中1例／2例呈阳性表达，且在各型之间没有显著性差异(P＞0．05)。结论 凋亡在脉络膜黑色素瘤中存在；Caspase-3在脉络膜黑色素瘤的发生发展中起重要作用。