Febrile seizures are the most common seizure type in young children. Whether they induce death of hippocampal and amygdala neurons and consequent limbic (temporal lobe) epilepsy has remained controversial, with conflicting data from prospective and retrospective studies. Using an appropriate-age rat model of febrile seizures, we investigated the acute and chronic effects of hyperthermic seizures on neuronal integrity and survival in the hippocampus and amygdala via molecular and neuroanatomical methods. Hyperthermic seizures-but not hyperthermia alone-resulted in numerous argyrophilic neurons in discrete regions of the limbic system; within 24 hr of seizures, a significant proportion of neurons in the central nucleus of the amygdala and in the hippocampal CA3 and CA1 pyramidal cell layer were affected. These physicochemical alterations of hippocampal and amygdala neurons persisted for at least 2 weeks but were not accompanied by significant DNA fragmentation, as determined by in situ end labeling. By 4 weeks after the seizures, no significant neuronal dropout in these regions was evident. In conclusion, in the immature rat model, hyperthermic seizures lead to profound, yet primarily transient alterations in neuronal structure.

Neuritic plaques are a pathological hallmark of Alzheimer's disease (AD). However, the origin of extracellular amyloid peptide (Aβ) deposits and the process of plaque development remain poorly understood. The present study attempted to explore plaque pathogenesis by localizing β-secretase-1 (BACE1) elevation relative to amyloid peptide (Aβ) accumulation and synaptic/neuritic alterations in the forebrain using transgenic (Tg) mice harboring familial AD (FAD) mutations (5XFAD and 2XFAD) as models. In animals with fully-developed plaque pathology, locally elevated BACE1 immunoreactivity (ir) coexisted with compact-like Aβ deposition, with BACE1-ir occurring selectively in dystrophic axons of various neuronal phenotypes or origins (GABAergic, glutamatergic, cholinergic or catecholaminergic). Prior to plaque onset, localized BACE1/Aβ-ir occurred at swollen presynaptic terminals and fine axonal processes. These BACE1/Aβ-containing axonal elements appeared to undergo a continuing process of sprouting/swelling and dystrophy, during which extracellular Aβ-ir emerged and accumulated in surrounding extracellular space. These data suggest that BACE1 elevation and associated Aβ overproduction inside the sprouting/dystrophic axonal terminals coincide with the onset and accumulation of extracellular amyloid deposition during the development of neuritic plaques in transgenic models of AD. Our findings appear in harmony with an early hypothesis that axonal pathogenesis plays a key or leading role in plaque formation.

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Cerebral hypometabolism, oxidative stress and beta-amyloid peptide (Abeta) accumulation are key pathological events in Alzheimer's disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Abeta genesis, is elevated in sporadic AD. Recent studies show BACE upregulation in experimental conditions likely associated with energy insufficiency and/or oxidative stress. We investigated the effect of sublethal doses of mitochondrial respiratory inhibitors and potential endogenous oxidative substances on BACE expression in vivo using the retina as a model. Retinas were analyzed biochemically and anatomically 48 h following intraocular applications of mitochondrial complex I, II and IV inhibitors including rotenone, 3-nitropropionic acid and sodium azide, and plaque-containing oxidants including Fe(3+) and Abeta42 fibrils (Abeta42f). All agents caused elevations of BACE proteins and beta-site amyloid precursor protein (APP) cleavage product, beta-CTF, in retinal lysates in a dose-dependant manner. BACE activity and Abeta40 levels were also increased in agent-treated retinas relative to vehicle controls. BACE immunoreactivity in normal adult rat retina was present mostly in the plexiform layers, indicating a localization of the enzyme to synaptic terminals. No apparent change in laminar or cellular distribution of BACE labeling was detected in the experimental retinas. However, signs of neuronal stress including glial activation were observed in agent-treated retinas especially in high dosage groups. Our data suggest that mitochondrial respiratory inhibition and oxidative stress facilitate BACE expression in vivo. In addition, plaque constituents such as Fe(3+) and Abeta42f may participate in a self-enforcing cycle of amyloidogenesis via BACE upregulation.

The aim of the study was to prospectively evaluate the clinical value of intravoxel incoherent motion (IVIM)-magnetic resonance imaging (MRI) in early predicting the treatment response to neoadjuvant chemotherapy (NAC) for nasopharyngeal carcinoma (NPC).Forty-eight patients with locoregionally advanced NPC were imaged with IVIM-MRI (14 b-factors, 0 – 1000 s/mm2) on a 3.0-T Magnetic resonance system, at the baseline, and repeatedly at the third and 21st day after NAC started. The IVIM-derived parameters (D, pure diffusion coefficient; f, perfusion fraction; and D∗, pseudodiffusion coefficient) were calculated with the Interactive Data Language version 6.3 software. The baseline parameters and their corresponding changes (Δparameter(day)) during NAC were compared using the Student t test or Mann-Whitney U test. Variation analyses of IVIM-derived parameters were tested with intraclass correlation coefficient. Receiver-operating characteristic (ROC) curve analysis was conducted to estimate the best diagnostic accuracy. Statistical analyses were performed on the SPSS 18.0 software, with a 2-tailed probability value, P < 0.05 was considered significant.Among recruited patients, 37 cases were categorized as responders and 11 cases as nonresponders after NAC completed. The intra- and interobserver intraclass correlation coefficient of IVIM-derived parameters were excellent, which ranged from 0.858 to 0.971. Compared with the baseline value, at the third and 21st day, the D value was significantly higher and the D∗ value significantly lower (P < 0.05, P < 0.001, respectively). In contrast, f parameter only changed slightly (P > 0.05). Compared with nonresponders, responders presented a notably lower baseline D value and higher ΔD3, ΔD21, ΔD3∗, ΔD21∗, and Δf21 (P < 0.05), but no significant change in Δf3 was observed (P > 0.1). The receiver-operating characteristic curve analyses indicated that the threshold of baseline D values that best predicted the responders for primary nasopharynx tumors and metastatic lymph nodes were 0.911 × 10−3 mm2/s versus 0.951 × 10−3 mm2/s, and their corresponding area under curve, sensitivity, and specificity were 0.714 versus 0.774, 0.658 versus 0.538, and 0.818 versus 0.944, respectively.IVIM-MRI can potentially early predict the treatment response of NAC for NPC patients. The baseline D value, and early changes in D and D∗ value are better predictors of the chemotherapeutic responsiveness.