Autism Research and Treatment 3 Table 2: Potential hypotheses for the relationship between autism and NF-kappaB. Autism literature Araghi-Niknam and Fatemi [63] showed a reduction of Bcl-2, an important marker of apoptosis, in the frontal, parietal, and cerebellar cortices of autistic individuals. Vargas et al. [37] reported altered cytokine expression proﬁles in brain tissue and cerebrospinal ﬂuid of patients with autism. Vargas et al. [37] also indicated that macrophage chemoattractant protein MCP-1 and tumor growth factor-beta1 were the most prevalent cytokines in the brain tissue of patients with autism. Ming et al. [46] reported on increased urinary excretion of an oxidative stress biomarker—8-iso-PGF2alpha in autism. Yoo et al. [65] observed statistically signiﬁcant associations between polymorphisms of PTGS2, the gene encoding cyclooxygenase-2, and autism spectrum disorders. Ma et al. [67] performed a genome-wide linkage analysis on 26 extended autism families and found signiﬁcant linkage to chromosome 12q14. Steele et al. [69] demonstrated spatial memory deﬁcits in high-functioning individuals with autism, particularly as tasks required heavier demands on working memory. Jyonouchi et al. [71] revealed intrinsic defects of innate immune responses in children with autism spectrum disorders and gastrointestinal symptoms. Grigorenko et al. [72] identiﬁed macrophage migration inhibitor factor, which is an upstream regulator of innate immunity, as a possible susceptibility gene for autism spectrum disorders. Johnson and Malow [74] highlighted frequent sleep problems among children with autism, such as obstructive sleep apnoea. surrounding these rare terms has an interesting term in common, this joint term is declared as a candidate for A (see Figure 1). The underlying assumption is that while the majority of the literature in any given ﬁeld describes matters related to common understanding of that ﬁeld, particular observations appearing rarely in the literature, may provide a promising direction towards novel discoveries. The method is called RaJoLink, which is derived from its three basic steps. (1) Step Ra: Identiﬁcation of interesting rare terms in the literature about C. (2) Step Jo: Search for a joint term, A, within the literature on the rare terms. (3) Step Link: Search for linking terms, B. For each B there should be a pair of articles, one from the literature on A and one from the literature about C, both mentioning B. All three steps are implemented in a user-friendly computer program. In all steps, expert involvement is crucial for the selection of terms obtained from the automatically generated sets of candidate terms. This ensures that results are in line with the expert’s interest and capture his or her NF-kappaB literature Mattson [29] reported that activation of NF-kappaB in neurons can promote their survival by inducing the expression of genes encoding antiapoptotic proteins such as Bcl-2 and the antioxidant enzyme Mn-superoxide dismutase. Ahn and Aggarwal [40] reported that, on activation, NF-kappaB regulates the expression of almost 400 diﬀerent genes, which include enzymes, cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors. Thibeault et al. [41] showed that the MCP-1 gene is expressed within particular populations of cells in response to inﬂammatory molecules that employ NF-kappaB as an intracellular signaling mechanism. Zou and Crews [64] reported an increase in NF-kappaB DNA binding following oxidative stress neurotoxicity. Lee et al. [66] elucidated the role of spinal NF-kappaB in the cyclooxygenase-2 upregulation and pain hypersensitivity following peripheral inﬂammation. Weersma et al. [68] mentioned chromosome 12q14 as a region of IRAK-M gene, which is an NF-kappaB-mediated negative regulator of the toll-like receptor/IL-1R pathways. Denis-Donini et al. [70] highlighted the function of NF-kappaB in hippocampal neurogenesis and in short-term spatial memory. Thomas et al. [39] conﬁrmed that NF-kappaB has a crucial and multifaceted role in innate immune responses. Gore et al. [73] showed that macrophage migration inhibitor factor regulates subsequent adaptive immune responses by initiating a signalling cascade that activates NF-kappaB. Yamauchi et al. [75] identiﬁed signiﬁcantly greater activation of NF-kappaB, which occurred in obstructive sleep apnoea. expertise in guiding the whole process. Further technical details on each of the steps have been described previously [12]. The aim of this paper is to present and to analyse, in detail, ﬁndings obtained when applying the RaJoLink me- thod in the ﬁeld of autism. Our hypothesis is that using the RaJoLink method we can identify relationships between biomedical concepts in disconnected sets of articles which might lead to a better understanding of the possible causes of autism. 2. Methods and Materials Publications about autism in the PubMed database served as a source of data. 10,821 publications were identiﬁed to August 21, 2006 as containing autis∗, the expression root for autism. There were 354 full text articles published in the PubMed Central database. Due to a noticeable shift in the research focus within these investigations, we further restricted the inclusion to those published in the last ten years. This resulted in a ﬁnal set of 214 publications.