Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation: immunohistochemical and immunoelectron microscopical analyses

To clarify the neuropathological significance of the deposition of N ^ɛ -carboxymethyl lysine (CML), an advanced glycation endproduct, in astrocytic hyaline inclusions in familial amyotrophic lateral sclerosis (FALS), autopsy specimens from five members of two different families who had the superoxide dismutase 1 (SOD1) gene mutations were analysed. Immunohistochemically, most of the neuronal and astrocytic hyaline inclusions were intensely stained by the antibody against CML. The distributions and intensities of the immunoreactivities for CML and SOD1 were similar in the inclusions in both cell types. Immunoelectron microscopy showed that both inclusions consisted of CML-positive granule-coated fibrils and granular materials. No significant CML or SOD1 immunoreactivity was observed in the neurons and astrocytes of the normal control subjects. Our results suggest that astrocytic hyaline inclusions contain CML and SOD1 in FALS patients with SOD1 gene mutations, and that the formation of CML-modified protein (probably CML-modified SOD1) is related to the cell degeneration. Received: 3 July 1998 / Revised, accepted: 21 September 1998     

Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain

Previous studies from our laboratory demonstrated that N(epsilon)-(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age-dependent manner. This suggests a potential link between AGE-accumulation and the aging process in neurons. The purpose of the present study was to examine whether this notion could be extended to other AGE structures, such as imidazolone and pentosidine. This was done using 19 human brains that were not affected by dementia. The immunohistochemical survey on distribution in brain tissues of imidazolone and pentosidine was carried out with monoclonal antibodies specific for imidazolone and pentosidine. A parallel control experiment was carried out with anti-CML antibody. The results showed that pentosidine and imidazolone were localized in neurons in different areas of human brain tissue, especially in neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine and imidazolone is very similar to that of CML. Furthermore, when the accumulation of these AGE structures was compared with the age of individual brains it was found that accumulation of imidazolone, pentosidine and CML in the CA4 region increased with age. These findings taken together support the notion that the accumulation of AGE structures in the CA4 region might be closely related to the aging process in neurons.     

IgE and FcɛRI regulation

The high-affinity immunoglobulin (Ig)E receptor, FcɛRI, regulates the action of mast cells and basophils and therefore, regulates the expression of atopic disease. There have been several recent observations that demonstrate new beaviors for this receptor. The control of FcɛRI expression, control of cell function by FcɛRI, and expression of FcɛRI on other cell types are important new areas of understanding currently being explored.     

APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.     

同种带瓣血管移植后免疫反应的研究

目的：研究同种带瓣血管移植后，受者的免疫反应及抗体变化。方法：选自１９９４年１０月至１９９５年２月间使用同种带瓣血管为补片材料的１２例先天性心脏病（先心病）患儿。取其移植前后的血清分别作为对照组与实验组。用免疫组化法，测定各血清与相应的供体动脉壁间的反应，观察抗体变化及抗原分布。结果：对照组及实验组术后７日内抗体检测为阴性；实验组术后第１０日、１４日抗体为阳性；抗原分布遍及动脉壁全层，但以内皮层最密集。临床上１２例患儿无死亡，未见发热等可能的免疫排斥现象，随访３～６个月，超声下未见有钙化及明显反流。结论：液氮保存的同种带瓣血管有抗原性，移植后可激活受体的免疫系统，产生特异性抗体，术前应做组织相容抗原（ＨＬＡ）及ＡＢＯ血型配型，并且术后短期使用免疫抑制剂。     

Inhibition of novel protein kinase Cɛ augments TRAIL-induced cell death in A549 lung cancer cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has great potential for cancer treatment since it provokes cell death in most tumor cells while leaving most normal cells unscathed. Some cancers, however, show resistance to TRAIL, indicating that TRAIL alone may be insufficient for cancer therapy. Here we studied whether the apoptotic susceptibility of A549 non-small cell lung cancer cells could be modulated by inhibiting protein kinase C (PKC). We show that an inhibitor with preference for novel PKC isozymes, NPC 15437, significantly augmented TRAIL sensitivity of A549 cells, as judged by assessing cell death and mitochondrial membrane potential. Likewise, NPC 15437 also significantly potentiated the responsiveness of DAOY medulloblastoma cells to TRAIL. In contrast, an inhibitor with preference for conventional PKC isozymes, Gö6976, did not augment TRAIL sensitivity of A549 cells. To further specify the PKC isozyme responsible for TRAIL sensitization, we used a peptide inhibitor with selectivity for the novel PKC isozyme ?, myr-PKC? V1-2. The inhibition of PKC? resulted in a significant amplification of the cytotoxic activity of TRAIL in A549 cells. Altogether, our study provides evidence for a considerable role of PKC? in the apoptotic responsiveness of A549 lung cancer cells, and possibly other malignancies, to TRAIL.     

Tubuloalveolar adenoma of salivary gland

An unusual monomorphic salivary gland adenoma, occurring in a 57-year-old woman, is described. The lesion was histologically similar to the so-called tubular adenoma; however, occasional microscopic foci of serous (acinar cell) differentiation were present. The term tubuloalveolar adenoma is proposed to describe salivary gland tumors that are histologically benign and composed of cells resembling those of normal intercalated ducts and secretory units (acini).     

Uterine choriocarcinoma with negative specific serum radioimmunoassay for human chorionic gonadotropins

A case of uterine choriocarcinoma complicating gestational trophoblastic disease is presented. Following chemotherapy, there seemed to be an apparent cure as indicated by follow-up monitoring of the beta subunit of human chorionic gonadotropin (B-HCG assay) when the assay demonstrated three consecutive weekly negative results. At the same period when the assays were negative, the patient was manifesting irregular vaginal bleeding for which diagnostic D&C was done revealing persistant disease which was not detected by measurement with the sensitive quantitiative B-HCG assay. The case is discussed to confirm the fact that clinical assessment is necessary for the follow-up of trophoblastic disease in addition to quantitative B-HCG.