Localized APP expression results in progressive network dysfunction by disorganizing spike timing.

Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.

Do or doughnut: A systematic review and pooled analysis on the utility of pathological evaluation of the anastomotic doughnut in oncological colorectal operations.

AIM: End-to-end anastomosis staplers are frequently used in colorectal surgery, generating two anastomotic doughnuts. Whether pathological evaluation of the doughnut changes clinical practice remains unclear. We aim to identify any effects of pathological evaluation of anastomotic doughnuts after oncological colorectal surgery. METHOD: We performed a systematic literature search utilizing PubMed, Clinicaltrials.gov, Cochrane, Embase and Web of Science databases and selected studies on evaluation of the anastomotic doughnut after oncological colorectal surgery with stapled end-to-end anastomosis. Outcome measures included: involved distal margin on the oncological sample, histological involvement of the doughnut, clinical change in management from a positive doughnut and study recommendations. RESULTS: Of the 5761 studies identified, eight studies encompassing 1754 patients were evaluated. Most operations were for primary colon (37.5%) or rectal adenocarcinoma (37.5%). Incidence of distal margin involvement of the oncological sample was reported in three papers, with six positive cases (1.1%). Of the 1754 doughnut pairs evaluated, five were positive for neoplasia (0.29%), three for adenomas (0.18%) and one for metaplastic polyp (0.06%), none of which changed postoperative treatment. Four studies recommended abandoning routine histopathological evaluation of anastomotic doughnuts, while the remaining four recommended evaluation only under certain criteria, including gross distal margin <2 cm (one study), gross distal margin <3 cm (one study), tumours undetected on gross examination (one study), 'histologically aggressive cancers' or grossly involved distal margin (one study). CONCLUSION: Routine evaluation of anastomotic doughnuts should be reconsidered, as <1% are positive for neoplasia. Exceptions may include specific scenarios where histopathology is likely to be clinically useful.