Neuropathology of ALS: Spheroids

I briefly review spheroids observed in the anterior horns of the spinal cord in amyotrophic lateral sclerosis (ALS). Spheroids are argentophilic bodies more than 20 μm in diameter. Recently, some connections between the proximal axonal swellings including spheroids and the perikarya have been reported in some ALS patients with a short clinical course or mild depletion of anterior horn neurons. Most of the cell bodies directly connected with the axonal swellings appear normal, and spheroids are considered to be one of the hallmarks of the early histological changes in this disorder. Spheroids are strongly positive with anti-phosphorylated neurofilament antibody, and are also positive with calcitonin gene-related peptide and anti-peripherin antibody. Some spheroids are immunostained with anti-synaptophysin antibody and anti-ubiquitin antibody. Spheroids are not immunostained with anti-phosphorylated tau antibody, or high molecular weight microtubule associated proteins. Electron microscopically, spheroids are usually composed of densely packed accumulation of 10 nm neurofilaments with a variety of orientations, plus vesicles, dense bodies and mitochondria. When the swellings of the initial segment is relatively pronounced, the undercoating is obscured and the neurofilaments become interwoven in some parts. In the first internode of the myelinated axons, as the swellings become larger, the neurofilaments lose their parallel orientation and become intermingled. Large accumulation of neurofilaments resembling spheroids in the perikarya of large anterior horn cells suggests that spheroids could be derived not only from the axon including the proximal portion, but also from the perikarya. Structures apparently identical to axonal spheroids are observed at the light and electron microscopic levels in the proximal portion of axons of anterior horn cells in animal models intoxicated with β, β'-iminodipropionitrile (IDPN), or with aluminum, in hereditary canine spinal muscular atrophy (HCSMA). The pathogenetic mechanism is probably associated with an impairment in slow axonal transport which particularly affects the neurofilaments in IDPN and aluminum intoxication. Impairment of slow axonal transport of neurofilaments also plays an important role in the pathogenesis of ALS. The average diameter of even normalappearing initial segment is larger in ALS than in the controls. The perikarya connected with the swollen proximal axons and their dendrites almost always appear normal. These findings suggest that the slow axonal transport of neurofilaments is probably impaired in this portion of the axon at an early stage in ALS as well as animal models for human ALS. However, techniques to analyze slow axonal transport in humans still remain tobe developed. Recently, overexpression of neurofilament subunits in transgenic mice produces a condition resembling ALS. The transgenic model may offer an interesting perspective not only for testing therapeutic strategies but also for investigating in a systematic way the various genetic and environment factors controlling the onset and progression of the disease and might yield new insights on the etiology of ALS.     

Multiple regression analysis of twin data obtained from selected samples

The multiple regression analysis of twin data in which a cotwin's score is predicted from that of a proband (the member of a twin pair selected because of a deviant score) and the coefficient of relationship provides a powerful test of genetic etiology (DeFries and Fulker: Behav Genet 15:467-473, 1985). Moreover, when an augmented model containing an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance owing to shared environmental influences (c2) are also obtained. In the present paper, the expected partial regression coefficients estimated from these models are derived, and the flexibility of the general approach is illustrated. An extended model is formulated for the analysis of data from combined samples of affected and control twin pairs that yields tests for differential h2 and c2 in the two groups as well as pooled estimates of these parameters. The application of these models is illustrated by an analysis of data from reading-disabled and control twin pairs. Because of the ease, flexibility, and utility of the multiple regression analysis of twin data, it is an appealing alternative to more traditional model-fitting approaches.     

大蒜素对脑局灶缺血大鼠血小板活化功能及其结构的影响

目的：观察大蒜素对脑局灶缺血大鼠血小板活化功能或轻药物诱导的血小板活化功能及其结构的影响。方法：（1）将SD大鼠随机分为（空白组、大蒜素大剂量组和小剂量组）3组，于末次给予试药1．5h后颈总动脉插管取血，加入诱导剂二磷酸腺苷（ADP）或胶原，测定血小板最大聚集率；（2）采用化学刺激（FeCl3)诱导血栓闭塞法制备大鼠急性大脑中动脉血栓模型，随机分为（假手术组、模型组、大蒜素大剂量组和小剂量组）4组，给药方法同实验（1），颈总动脉插管取血后分离血浆，测定血浆血栓烷B2（TXB2）、6－酮－前列腺素F1α(6-keto-PGF1α）含量；（3）加入ADP孵育激活性，离心得到血小板沉淀块，透射电镜下观察血小板的超微结构。结果：与空白组或模型组相比，大蒜素大剂量组（10mg/kg)、小剂量组（5mg/kg)均可显著抑制药物诱导的血小板聚集（P＜0．01），且大剂量组显著优于小剂量组（P＜0．05）；均可明显降低模型大鼠血浆TXB2的含量，降低TXB2／6－keto-PGF1α比值，大剂量组还显著升高血浆中6－keto-PGF1α水平（P＜0．05，P＜0．01）；可明显抑制血小板活化过程中超微结构的改变，且有一定的量效关系。结论：大蒜素可能通过抑制血小板聚集，抑制血小板活化时大量释放的活性肽TXA2、促进恢复TXA2／PGI2平衡，抑制血小板激活释放过程中超微结构的改变，从而对脑梗塞起治疗作用。     

Muscle mass index in haemodialysis patients: a comparison of indices obtained by routine clinical examinations.

BACKGROUND: Measurement of muscle mass is useful for evaluating protein nutritional status. Various methods for estimating muscle mass in haemodialysis patients have recently been developed. METHODS: The validity of the estimate of creatinine production calculated with the creatinine kinetic model (CKM) was examined in 46 haemodialysis patients by comparing it with the actual creatinine production, this being determined from the sum of creatinine appearing in the dialysate and the estimated metabolic degradation. The correlation of various other muscle mass indices with creatinine production was also investigated in these patients. RESULTS: The estimate of creatinine production using CKM was significantly correlated with creatinine production calculated from the spent dialysate plus an estimate for the extra-renal creatinine degradation (r=0.90, P<0.001). A Bland-Altman analysis revealed that the mean prediction error for the estimate of creatinine production by CKM was +0.10 g/day and the limits of agreement were +0.34 to -0.14 g/day. The cross-sectional area of the thigh muscle measured by computed tomography (CT) was also significantly correlated with creatinine production (r=-0.86, P<0.01). In contrast, the correlations of 3-methylhistidine production measured in the spent dialysate, the mid-upper arm muscle circumference and the skeletal muscle mass estimated by an anthropometric prediction model with creatinine production were lower (r<0.82). CONCLUSION: Creatinine production calculated using CKM and CT measurement of thigh muscle area are valid methods for estimating muscle mass during routine clinical examinations of haemodialysis patients.     

影响利培酮治疗精神分裂症疗效因素分析

目的　探讨影响利培酮对精神分裂症疗效的关键因素。方法　对 57例单用利培酮治疗的精神分裂症患者 ,采用一系列标准评定工具对 39个临床指标进行定量或半定量评估。并作Logistic回归分析。将治疗后简明精神病评定量表 (BPRS)减分率≥ 30 %者确定为“有效”。结果　单因素分析显示 :服药依从性 ,MMPI中Sc、Si、D因子 ,治疗前BPRS 2和BPRS 4因子 ,TESS 3因子 ,家族史 ,起病形式 ,意识模糊 ,住院时间与利培酮疗效有关 ;经多因素分析有服药依从性 ,MMPI(Sc) ,BPRS 2 ,家族史 ,意识模糊等 5个指标选入回归方程。结论　影响利培酮对精神分裂症疗效的关键因素依次为服药依从性 ,MMPI中精神分裂因子 ,阴性症状 ,家族史及意识模糊     

Spontaneous regression of a temporal arachnoid cyst

Surgery is considered to be the standard therapy for arachnoid cysts (ACs). We report the case of a 13-year-old boy in whom a right temporal AC disappeared spontaneously over a period of 10 years. Bulging of the right temporal skull led to the detection of the cyst by computed tomography (CT) scan at the age of 3 years. There were no other clinical symptoms. Subsequent CT scans showed spontaneous regression of the cyst without surgical intervention. The question as to how ACs should be treated is discussed.     

Sex effects in defensive behavior: Baseline differences and drug interactions

Female rats consistently show a pattern of differences in defensive behaviors compared to males which parallel the effects of exposure to a nonpainful threat stimulus (cat or cat odor) in the same tests and measures. These indications of greater defensiveness for females are particularly common in situations involving potential, as opposed to actual and present, threat, a factor which probably also reflects ceiling or floor effects in situations involving very intense defensiveness. In addition, pharmacological studies indicate sex differences in the effects of selective serotonin (5-HT) receptor agonists and antagonists on defensive responding. These findings indicate that sex effects must be considered in studies of the pharmacological control of defensive behaviors, and suggest that responsivity to sex effects may be an additional criterion for the suitability of animal models of anxiety.     

烹调油烟致大小鼠肺癌的实验研究

[目的]了解烹调油烟（cooking oil fumes，COF）的动物致癌性。[方法]采用动式染毒法给Balb／c小鼠（雌雄各半）吸入COF浓度为9．09、20．65、38．85mg／m^3，染毒1次／1～2d，30min／次，共150次，计8个月；SD大鼠（雌雄各半）吸入COF浓度为6、88、15．06、35．33mg／m^3，染毒1次／2d，30min／次，共191次，计12．5个月。分别制备COF慢性中毒动物模型；两实验均设空白对照组，吸入与实验组相同温度的清洁空气。[结果]COF诱发Balb／c小鼠实验组肺癌总发生率为18、95％（29／153），低、中、高浓度组肺癌发生率分别为15．09％、20、00％和22．00％，与对照组差异均有显著性。但低、中、高三组间差异无显著性（P〉0．05）；COF诱发SD大鼠肺癌总发生率为9、10％（9／99），低、中、高浓度组肺癌发生率分别为6．45％、8．57％、12．12％，高浓度组肺癌发生率高于对照组（P〈0．05）。各性别组间肺癌发生率的差别无显著性（P〉0．05）。[结论]COF可以诱导Balb／c小鼠和SD大鼠肺癌，诱发的肺癌主要为肺腺癌（小鼠28／29，大鼠7／9），余为小细胞肺癌。     

草分支杆菌疫苗治疗哮喘模型小鼠的实验研究

目的　研究草分支杆菌疫苗对哮喘模型小鼠的疗效及其作用机制。方法　将 18只BALB/c小鼠分为3组 ,每组各 6只 ,其中卵蛋白致敏哮喘组 (OVA组 )和草分支杆菌疫苗治疗组 (Utilin组 )皮下注射卵蛋白致敏制作哮喘模型 ,然后用卵蛋白激发 2次 ;阴性对照组 (NS组 )皮下注射生理盐水 (NS) ,然后NS激发 2次。Utilin组在激发前后分别给予草分支杆菌疫苗 0 .5 μg腹腔注射 3次 ,其他两组不作干预。 3组分别在第 2次激发后第 1、2、3、4周眼眶后静脉丛采血测OVA特异性免疫球蛋白IgE ,并于激发后第 4周处死小鼠测肺泡灌洗液 (BALF)中的细胞总数及嗜酸性粒细胞 (EOS)计数 ,肺组织病理切片观察形态学改变 ,并测定脾细胞培养上清液中OVA特异性IFN γ。结果　Utilin组BALF中细胞总数为 (2 9.5 1± 5 .81)× 10 4 /mL、EOS为 (2 .88± 0 .96 )× 10 4 /mL ,明显低于OVA组 [分别为 (4 0 .15± 6 .12 )× 10 4 /mL和 (6 .91± 1.92 )× 10 4 /mL],P <0 .0 5 ;Utilin组肺组织炎症反应较OVA组明显减轻 ;Utilin组脾细胞培养上清液中OVA特异性IFN γ的浓度为 (4 6 9± 86 )pg/mL ,明显高于OVA组 (193± 80 ) pg/mL ,P <0 .0 5 ;Utilin组激发后第 3周和第 4周OVA特异性IgE分别为 (0 .2 99± 0 .0 92 )(OD值 ) ,(0 .2 6 7± 0 .0     

Modelling Germline Mosaicism and Different New Mutation Rates Simultaneously for Appropriate Risk Calculations in Families with Duchenne Muscular Dystrophy

For several genetic diseases two biological phenomena have been recognised as important: germline mosaicism; and different new mutation rates in males and females depending on mutation type. Both principles have been investigated separately and their influence on risk estimation in families has been exemplified in the literature. The aim of this paper is to present a general model that includes mosaicism and different new mutation rates. Mosaicism is introduced by defining additional alleles at the disease locus in combination with adapted segregation rules. Taking Duchenne muscular dystrophy as an example, we derive the conditions which have to be fulfilled for a population in mutation selection equilibrium. Our approach describes the model at the population level and not in individual subjects. This has the advantage of being able to use well known algorithms for the calculation of likelihoods in pedigrees, and to include additional diagnostic information such as marker genotypes and carrier deletion test results. We demonstrate the impact of the new model on a typical pedigree. In families where the patient is not available, the distinction between point mutations and deletions is important, since often molecular diagnostic tests for females can only screen for deletions. Negative deletion test results can now be included in the risk calculations.