PET network abnormalities and cognitive decline in patients with mild cognitive impairment.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01-0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considered.     

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling

Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.      

Positron emission tomographic measurement of blood-to-brain and blood-to-tumour transport of 82Rb. I: Error analysis and computer simulations

Unidirectional blood-to-brain and blood-to-tumour transport rate constants (K1) for 82Rb (half-life 76 s) and plasma water volume per unit mass of brain/tumour tissue (Vp) can be estimated in vivo using dynamic positron emission tomography (PET). The accuracy of these estimates depends upon the accuracy of PET measurements of regional brain/tumour radioactivity and scintillation well detector measurements of whole-blood radioactivity, which, in turn, depend upon the time course of arterial blood radioactivity. A two-compartmental model has been employed to derive estimates for K1, k2 (efflux rate constant) and Vp from 82Rb/PET data. Errors in these parameter estimates have been studied (1) qualitatively using sensitivity function analysis and (2) quantitatively using computer simulations. The effect of adding a third irreversible compartment and its unidirectional rate constant, k3, has also been investigated. The advantages and disadvantages of bolus injection vs continuous infusion protocols are discussed. Precision in estimated parameters from actual patient data is compared to that obtained from computer simulations in part II of this paper.     

Die normale Nierensch Welle für Glucose bei langdauernder Zuckerbelastung

Zusammenfassung An 21 Patienten wurde die Harnschwelle für Zucker, die tubuläre Rückresorptionskapazität und die Zuckerausscheidung bestimmt. Hierbei ergab sich bei langdauernder Zuckerbelastung eine absolute Vergrößerung der ausgeschiedenen Zukkermengen mit Abfall der Harnzuckerschwelle. Diese Verminderung wurde durch einen absoluten Abfall der tubulären Rückresorptionskapazität und relativen Abfall im Verhältnis zur filtrierten Zuckermenge hervorgerufen. Diese Einschränkungen traten mit zunehmender Versuchsdauer in Erscheinung und werden auf eine Erschöpfung der tubulären fermentativen Vorgänge bezogen. Vielleicht finden hierin auch die anderweitig beobachteten tubulären Degenerationen bei langdauernder Zuckerbelastung ihre Erklärung. Eine länger dauernde Glykosurie scheint für die Tubulusepithelien eine echte Belastung darzustellen.Diese Arbeit ist meinem Chef, Herrn Prof.Wollheim, zu seinem 60. Geburtstag am 24. 3. 60 gewidmet.     

Reporter gene assay for fish-killing activity produced by Pfiesteria piscicida.

Collaborative studies were performed to develop a functional assay for fish-killing activity produced by Pfiesteria piscicida. Eight cell lines were used to screen organic fractions and residual water fraction by using a 3-[4, 5-dimethylthiazol-(2-4)]-diphenyltetrazolium bromide cytotoxicity assay. Diethyl ether and a residual water fraction were cytotoxic to several cell lines including rat pituitary (GH(4)C(1)) cells. Residual water as well as preextracted culture water containing P. piscicida cells induced c-fos-luciferase expressed in GH(4)C(1) cells with a rapid time course of induction and sensitive detection. The reporter gene assay detected activity in toxic isolates of P. piscicida from several North Carolina estuaries in 1997 and 1998 and may also be suitable for detecting toxic activity in human and animal serum.