The number of times an article is cited in scientific journals reflects its impact on a specific biomedical field or specialty and reflects the impact of the authors' creativity. Our objective was to identify and analyze the characteristics of the 100 most frequently cited articles published in journals dedicated to general surgery and its close subspecialties. Using the database (1945-1995) of the Science Citation Index of the Institute for Scientific Information, 1500 articles cited 100 times and more were identified and the top 100 articles selected for further analysis. The 100 articles were published between 1931 and 1990, with more than two-thirds of them published after 1960. The mean number of citations per article was 405, (range 278-1013). Altogether, 84 of the articles originated from North America (USA 78, Canada 6) and the UK (12). New York State led the list of U.S. states with 14, and Harvard and Columbia University led the list of institutions with 6 articles each. The 100 articles were published in 10 surgical journals led by the Annals of Surgery (n = 40), followed by Surgery (n = 15), Archives of Surgery (n = 12), Surgery, Gynecology and Obstetrics (n = 11), and British Journal of Surgery (n = 10). A total of 80 of the articles reported clinical experiences, 6 were clinical review articles, and 14 dealt with basic science. Eighteen articles reported a new surgical technique and six a prosthetic device. Gastrointestinal surgery and trauma and critical care led the list of the surgical fields, each with 25 articles, followed by vascular surgery (n = 15). Thirty-four persons authored two or more of the top-cited articles. This list of the top-cited papers identifies seminal contributions and their originators, facilitating the understanding and discourse of modern surgical history and offering surgeons hints about what makes a contribution a "top-cited classic." To produce such a "classic" the surgeon and his or her group must come up with a clinical or nonclinical innovation, observation, or discovery that has a long-standing effect on the way we practice-be it operative or nonoperative. Based on our findings, to be well cited such a contribution should be published in the English language in a high-impact journal. Moreover, it is more likely to resonant loudly if it originates from a North American or British "ivory tower."

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

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