Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice

Missense mutations in the beta-amyloid precursor protein gene (APP) co- segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.      

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

Gliomatosis cerebri: cytologic and autopsy findings in a case involving the entire neuraxis.

We describe the case of a 7-year-old girl who was clinically diagnosed as having a pontine glioma based on magnetic resonance imaging studies. Neoplastic cells were identified upon cytologic examination of cerebrospinal fluid. Autopsy studies revealed an anaplastic astrocytoma (WHO grade III) diffusely infiltrating the cerebral hemispheres, brain stem, cerebellum, leptomeninges, and spinal cord to the level of the conus medullaris. The Ki-67 labeling index focally approached 30%. Although many of the neoplastic cells displayed elongated twisted nuclei reminiscent of microglia, these cells stained intensely for glial fibrillary acidic protein, supporting an astrocytic origin. Unusual features of this case of gliomatosis cerebri include involvement of the entire central neuraxis, correlation with pre-mortem lumbar puncture cytology, and a markedly elevated Ki-67 labeling index.     

阿霉素羧甲基葡聚糖微球犬肝动脉栓塞后阿霉素的体内过程

研究了阿霉素羧甲基葡聚糖微球经肝动脉栓塞后的体内动力学过程、靶向特征和微球在体内的肝动脉栓塞效果。对犬进行肝动脉栓塞实验,并与肝动脉阿霉素(ADM)溶液灌注组进行对照。用HPLC荧光检测外周静脉和组织中药物浓度。结果表明:微球组峰浓度为0.558μg/ml,溶液组为1.013μg/ml;微球组的T_1/2(α),T_1/2(β)和MRT分别为溶液组的2.82,3.19和1.28倍。栓塞不同部位组织中ADM浓度,微球组分别是溶液组的8.0和9.1倍。动态血管造影表明:肝内外未见侧枝循环形成,栓塞作用持久,16周后微球仍未见完全降解。     

Coarctation of the aorta: MR imaging

Thirteen patients, aged 3-31 years, with coarctation of the thoracic aorta were examined by magnetic resonance (MR) imaging (total of 14 studies). Eight studies were performed preoperatively and six postoperatively. Catheterization data were available on 12 patients for verification of MR imaging findings. Electrocardiographically gated sagittal and left anterior oblique images best depicted the coarctations; however, involvement of arch vessels was best evaluated on transaxial images. MR imaging readily identified all coarctations but one, their site and extent, and involvement of the arch vessels. In addition, MR images depicted poststenotic dilatation and dilated collateral vessels. In patients studied postoperatively, restenosis could be evaluated, and complications such as postoperative aneurysm and perianastomotic hematoma were identified. MR imaging provides excellent anatomic detail of coarctation of the aorta, potentially obviating the need for angiography.     

Pulmonary edema: an MR study of permeability and hydrostatic types in animals

Permeability pulmonary edema was induced in ten rats by intravenous injection of oleic acid. Hydrostatic pulmonary edema was induced in another ten rats by continuous infusion of saline. Permeability pulmonary edema was detected as increased signal intensity in all animals on images obtained with repetition times (TR) of 2.0 sec and echo times (TE) of 28 and 56 msec. Hydrostatic pulmonary edema was perceivable only in seven of ten rats. It was best seen on spin-echo TR = 2.0 sec, TE = 28 msec images as increased intensity either throughout the whole lung or in a predominant central distribution. The slopes of the relationships between the mean signal intensity and water content of both lungs were lower for hydrostatic pulmonary edema than for permeability pulmonary edema. Hydrostatic pulmonary edema demonstrated similar T1 but markedly shorter T2 relaxation times than permeability edema. Magnetic resonance imaging can be used to estimate severity of hydrostatic and permeability pulmonary edemas.     

Delayed rupture of renal artery after renal percutaneous transluminal angioplasty

Two cases are reported in which rupture of the renal artery occurred many hours after renal percutaneous transluminal angioplasty. Delayed rupture can be recognized by the angiographic appearance and by the presence of persistent flank pain. The typical angiographic finding is a poorly defined zone of contrast medium at the site of perforation.