Concomitant LATE-NC in Alzheimer's disease is not associated with increased tau or amyloid-ß pathological burden.

AIMS: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. METHODS: A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-ß in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. RESULTS: LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P = 0.009). CONCLUSION: The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or Aß pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.

Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent.

We recently generated an advanced mouse model of Alzheimer's disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4-12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.

Synthetic modification of a novel microbial ionophore: exploration of anticoccidial structure-activity relationships.

While fermentation-derived polyether ionophores such as salinomycin are the dominant class of anticoccidial feed additives, there is little information concerning the structural features which confer optimal potency/efficacy in this important series. The recently discovered microbial polyether 1a, featuring potent, broad-spectrum anticoccidial activity, was employed as a template to explore structure-activity relationships. A number of single-step synthetic modifications targeted structural changes in both the lipophilic carbon backbone and the ion-binding cavity of 1a. Although previous semisynthetic transformations among the polyether ionophores almost always resulted in a substantial loss of anticoccidial activity, we obtained several analogues, altered on the periphery of the ionophore-ion complex, which retain good potency and efficacy. Monoglycone 7 (semduramicin sodium) has the most impressive anticoccidial profile of this series, and is undergoing further biological testing under field conditions.

Evaluation of a comprehensive elementary school curriculum-based drug education program.

This study was designed to evaluate the effectiveness of a province-wide chemical abuse prevention education program for grades two through six. Two separate studies were conducted. Study 1 measured pre- and post-scores on a test with 1101 experimental and 991 control subjects in a quasi-experimental design. Study 2 surveyed 500 elementary school teachers on their opinions and practices regarding drug education, and on the prevalence of the program in schools. The study found that: 1) students had a high initial knowledge level; 2) students showed modest but statistically significant knowledge gains for urban schools and grades three, four, and five of rural schools; 3) the program was most effective with students with a low base knowledge; 4) an estimated 20 to 30 percent of Manitoba elementary teachers had been in-serviced and/or were using the program across the province; and 5) the program was received well among teachers.

[Longterm study of the effectiveness of different dental care programs in school children]. / Langzeitstudien zur Effektivität von unterschiedlichen Betreuungsstrategien bei Schulkindern.

The caries prevalence was examined in children from the first to the tenth grade in Rostock and Krakow between 1974 and 1988. In Krakow, a town with a preventive orientated dental care program, a significance caries reduction was found. Therefore there is an increase of health and an improvement of oral situation for the children on the way to the goals of WHO for oral health by the year 2000.