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.     

Structural modification of receptor-binding technetium-99m complexes in order to improve brain uptake

Low brain uptake is a generally accepted problem in developing technetium-99m brain receptor imaging agents. For a class of potential 5-HT_2A receptorbinding agents we tried to improve the original low brain uptake of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pK _a value leads to ionization of the molecule at blood pH, the pK _a value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pK _a value from 10.0 to 8.3 and dramatically increases the brain uptake to 1.3% ID at 5 min. The direct relationship between brain uptake and apparent pK _a cannot be simply explained by the increase in the pK _a-governed proportion of the neutral species.     

Synthetic Colloids Attenuate Leukocyte-Endothelial Interactions by Inhibition of Integrin Function

Background: It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions.

Methods: Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm2. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils.

Results: Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins.     

Transgenic expression of a CD46 (membrane cofactor protein) minigene: Studies of xenotransplantation and measles virus infection

CD46 (membrane cofactor protein) is a human cell-surface regulator of activated complement and a receptor for the measles virus. A CD46 transgenic mouse line with an expression pattern similar to that of human tissues has been produced, to develop an animal model of (i) the control of complement activation by complement regulators in hyperacute rejection of xenografts, and (ii) measles virus infection. The mouse line was made using a CD46 minigene that includes promoter sequence and the first two introns of genomic CD46, which was coinjected into mouse ova with chicken lysozyme matrix attachment region DNA. A high level of CD46 expression in homozygotic transgenic mice was obtained with spleen cells having approximately 75% of the level found on human peripheral blood mononuclear cells. CD46 was detected in all tissues examined by immunohistochemistry, radioimmunoassay and Western blotting, showing that these mice were suitable for transplantation and measles virus infection studies. It also indicated that the transgene included the important regulatory elements of the CD46 promoter. Transgenic spleen cells were significantly protected in vitro from human complement activated by either the classical or alternative pathways and from alternative pathway rat complement. Furthermore, transgenic mouse hearts transplanted to rats regulated complement deposition in an in vivo model of antibody-dependent hyperacute xenograft rejection. Similar to human lymphocytes, transgenic lymphoblasts could be infected in vitro with measles virus; infected cells expressed viral proteins and produced infectious viral particles. The data demonstrate the suitability of this minigene for obtaining high-level CD46 expression sufficient for enhanced resistance of transgenic cells to complement attack and for obtaining wide tissue distribution of CD46, analogous to human tissues and, therefore, useful for comparative studies.     

Somatoform pain disorder in the general population

BACKGROUND: Chronic pain disorder is assumed to represent a frequent and disabling condition. However, data on the prevalence of somatoform pain symptoms and somatoform pain disorder in the community are limited to date. METHODS: German versions of the Composite International Diagnostic Interview were administered to a representative national sample of 4,075 people. Somatoform pain disorder was diagnosed by standardized diagnostic algorithm based on the DSM-III-R criteria (absence of adequate physical findings). One subgroup was identified as also meeting the DSM-IV criterion B for 'significant distress or psychosocial impairment due to the somatoform pain'. RESULTS: A lifetime prevalence rate of somatoform pain disorder according to DSM-III-R of 33.7% and a 6-month rate of 17.3% was found. When applying the DSM-IV B criterion, the prevalence rate dropped to 12.3 and 5.4%, respectively. In both groups more than 95% of the probands had contacted their doctor because of the pain. In 25% of the probands the pain was positively assigned to psychological factors. A female:male ratio of 2:1 was found. CONCLUSIONS: Somatoform pain disorder (DSM-III-R) is a frequent condition. However, only about one third of these subjects is severely distressed or impaired by the pain. A clear operationalized concept of the DSM-IV criterion C 'psychological factors are judged to have an important role in the onset, severity, exacerbation or maintenance of the pain' should be provided in the further development of the diagnosis 'pain disorder' in order to make this diagnosis suitable for general population surveys.     

Molecular characterization of a serotype O121:H19 clone,a distinct Shiga toxin-producing clone of pathogenic Escherichia coli

Most illnesses caused by Shiga toxin-producing Escherichia coli (STEC) have been attributed to E. coli serotype O157:H7, but non-O157 STEC infections are now increasingly recognized as public health problems worldwide. The O121:H19 serotype is being isolated more frequently from clinical specimens and has been implicated in one waterborne outbreak. We used multilocus virulence gene profiling, a PCR-based assay, to characterize the virulence gene content of 24 isolates of serotype O121:H19 and nonmotile variants. We also performed multilocus enzyme electrophoresis and multilocus sequencing to establish the clonal relatedness of O121 isolates and to elucidate the relationship of O121 to common STEC clones. The 24 isolates were found to represent a single bacterial clone, as there was no allelic variation across 18 enzyme loci among the isolates. The complete nucleotide sequence of the intimin gene differed by four substitutions from that of the epsilon (Int- epsilon ) allele of O103:H2 strain PMK5. The typical O121 virulence gene profile was similar to the profiles of enterohemorrhagic E. coli (EHEC) clones of E. coli: it included a Shiga toxin 2 gene (stx(2)), two genes on the EHEC plasmid (toxB and ehxA), and the gene encoding intimin (eae). Despite the similarities, putative virulence genes distributed on O islands-large chromosomal DNA segments present in the O157:H7 genome-were useful for discriminating among STEC serotypes and the O121:H19 clone had a composite profile that was distinct from the profiles of the other major EHEC clones of pathogenic E. coli. On the basis of sequencing analysis with 13 housekeeping genes, the O121:H19 clone did not fall into any of the four classical EHEC and enteropathogenic E. coli groups but instead was closely related to two eae-negative STEC strains.