Morphologically distinct plaque types differentially affect dendritic structure and organisation in the early and late stages of Alzheimer's disease

We have investigated the effects of the deposition of insoluble beta-amyloid plaques on dendritic morphology within the neocortex. Labelling for beta-amyloid identified three morphologically distinct plaque types present both within the brains of preclinical Alzheimer's disease (AD) and end-stage AD cases. In both preclinical and end-stage AD, the percentage area occupied by diffuse plaques contained a greater density of labelling for microtubule-associated protein-2 (MAP2) relative to the surrounding neuropil (case type, ratio of MAP2 labelling in plaque to MAP2 labelling in surrounding neuropil +/- SEM: preclinical, 1.27+/-0.04; end-stage, 1.32+/-0.05). In contrast, there was a greater density of MAP2-labelled processes surrounding dense-cored plaques compared to that found within the plaque area (preclinical, 0.73+/-0.05; end-stage, 0.62+/-0.07). Fibrillar plaques demonstrated a transition from the early to late stages of AD, with a substantial decrease in the density of MAP2 labelling within the plaque area in end-stage AD cases relative to preclinical AD cases (preclinical, 1.01+/-0.1; end-stage, 0.72+/-0.05). The morphology of dendrites associated with dense-core or fibrillar plaques suggest physical disruption of the neuropil by beta-amyloid plaque formation. These data demonstrate that plaque isoforms differentially affect dendritic morphology in both the early and late stages of AD, with progression to clinical AD associated with evolving dendritic damage localised to fibrillar and dense-core plaques.     

Colorectal hepatic metastases: resection, local ablation, and hepatic artery infusion pump are associated with prolonged survival

BACKGROUND: Treatment of metastatic colorectal cancer to the liver is not uniform. We describe the management of metastatic colorectal cancer of the liver at a single institution during a 10-year period. METHODS: From January 1, 1990, through December 31, 1999, 174 patients were identified from the tumor registry at the University of Alabama at Birmingham with a diagnosis of metastatic colorectal cancer to the liver. Patient, tumor, laboratory, operative, and adjuvant therapy factors were analyzed, with overall survival as the endpoint. Log-rank tests were used for univariate analysis, Cox-proportional hazards model for multivariate analysis, and Kaplan-Meier curves were used for graphical representation of survival. Significance was defined as P<.05. RESULTS: Median age was 60 years (age range, 18-92 years). Seventy-nine percent of patients had synchronous liver metastases at the time of diagnosis of the primary colorectal tumor. The primary tumor was in the colon and rectum 75% and 25% of the time, respectively. Of the 89 patients who underwent operation, 73 received definitive surgical treatment for their liver metastases. Fifty-two patients underwent lobectomy or wedge resection, 5 underwent cryotherapy, and 16 had a hepatic artery infusion pump (HAIP) inserted. Median follow-up duration of surgically treated patients was 26 months. Operative mortality was 1.3%. The 3-year actuarial survivals for patients who underwent resection, HAIP, or those with unresectable disease were 70 months, 32 months, and 3 months, respectively (P<.001). By multivariate analysis, surgical intervention, a carcinoembryonic antigen level less than 200 microg/L, or a low T stage of the primary tumor were associated with prolongation of survival. CONCLUSIONS: Surgical resection should be attempted for hepatic colorectal metastases, as this is associated with prolonged overall survival. Hepatic artery infusion pump insertion seems to prolong overall survival for those with unresectable hepatic metastases, but it is not equal to resection. Aggressive surgical management of patients with hepatic colorectal metastases is safe, may prolong overall survival, and therefore should be considered in all patients with metastases confined to the liver.     

Molecular analysis of PKU in Ireland

Classical phenylketonuria (PKU: McKusick No. 261600) is caused by mutations occurring at the phenylalanine hydroxylase (PAH) locus on chromosome 12 and has a prevalence in Ireland of 1 in 4500. We examined 304 independent alleles from 350 patients for the presence of six mutations and have characterized VNTR alleles within the minisatellite region 3' to the PAH gene in patients carrying the most prevalent mutation. R408W was the most common mutation found, with a relative frequency of 42%. All other mutations had relative frequencies of <10%. VNTR analysis showed that the R408W mutation is associated with the VNTR-8 allele in the Irish population, indicating that R408W is associated with RFLP haplotype 1. This differs from that reported from eastern Europe where R408W is associated with RFLP haplotype 2/VNTR-3; an observation which has led several groups to propose a Balto-Slavic origin for this mutation. These results support the hypothesis of a second, independent founding event for the R408W mutation on an RFLP haplotype 1 VNTR-8 chromsome background in the Irish/Celtic population.     

Metabolism of methyldopa in man after oral administration of the pivaloyloxyethyl ester

In a crossover study, the pivaloyloxyethyl ester (POE) of methyldopa, labeled either with 3H in the methyldopa moiety or 14C in the pivalic acid moiety, was administered orally to four volunteers in 1000-mg single doses (equivalent to 500 mg of methyldopa). The majority (93%) of either the 3H- or 14C-labeled dose was excreted in the urine. Methyldopa, which was assayed by a fluorometric technique, peaked (approximately 6 micrograms/ml) at 1 hr in the plasma. Forty-five per cent of the dose was excreted as methyldopa as opposed to 18% normally seen after oral methyldopa dosages. Intact POE was absent in the urine of three volunteers and present in only trace amounts in urine from a fourth volunteer. Thus, the oral dose of POE was well absorbed and rapidly hydrolyzed to methyldopa. After oral administration of methyldopa, methyldopa sulfate is the principal urinary metabolite in man. However, after administration of POE, a relatively small fraction (13%) of the dose was excreted as methyldopa sulfate. The major urinary metabolite of POE, other than methyldopa, was 3-OCH3 methyldopa. Methyldopamine was a minor metabolite. It was concluded that a shift from sulfation to methylation occurred in the metabolic profile of methyldopa when it was administered as POE and that the metabolites of POE (including conjugated pivalic acid) were rapidly eliminated from the body.