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Competing Interests: Competing interests: None declared.

Post-traumatic stress disorder (PTSD) is a risk factor in the development and progression of Alzheimer's disease (AD), with unclear underlying mechanisms. Recently, we provided data showing the effect of trauma-like stress on Bin1 and Fkbp5 expression in the prefrontal cortex of Aβ (1-42) lesioned animals. This present work sought to expand the study by examining the involvement of the amygdala and hippocampus, in addition to highlighting the role of NR2B in the co-occurrence of trauma-like stress and an Aβ AD-like pathology. Trauma-like condition was induced by exposing the animals to footshocks. Aβ (1-42) was injected into the hippocampus of the animals to induce AD-like pathology. Cognitive functions were assessed in the Morris water maze (MWM) and novel object recognition tests, after which amygdala and hippocampus tissues were harvested for neurochemical analyses. We found that the combination of footshocks and Aβ (1-42) lesion caused a decrease in the number of crossings in the target quadrant of the Morris water maze test, indicating memory deficits. Footshocks caused a further downregulation of Bin1 in the amygdala of Aβ (1-42) -lesioned rats. Prior exposure to footshocks downregulated NR2B in the hippocampus of Aβ (1-42)- lesioned rats. In addition, a combination of footshocks and Aβ (1-42) lesion sustained the upregulation of Fkbp5 in the hippocampus and amygdala. A combination of footshocks and Aβ (1-42) lesion increased neuronal apoptosis in the hippocampus and amygdala. In conclusion, exposure to a trauma-like condition may influence AD-like pathology, leading to exaggerated behavioural and molecular changes in the amygdala and hippocampus., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) affects several brain areas, including the prefrontal cortex (PFC) involved in execution, working memory, and fear extinction. Despite these critical roles, the PFC is understudied in AD pathology. People with post-traumatic stress disorder (PTSD) have twice the risk of developing AD, and the underlying mechanisms linking these two diseases are less understood. Here, we investigated the effect of footshock stress on behavioural vis-a-vis molecular changes in the PFC of an amyloid-beta (Aβ)-42 lesion rat model of AD. Trauma-like conditions were induced by exposing the animals to several footshocks. AD-like condition was induced via intra-hippocampal injection of Aβ-42 peptide. Following Aβ-42 injections, animals were tested for behavioural changes using the Open Field Test (OFT) and Y-maze test. The PFC was later harvested for neurochemical analyses. Our results showed an interactive effect of footshocks and Aβ-42 lesion on: reduced percentage alternation in the Y-maze test, suggesting memory impairment; reduced number of line crosses and time spent in the centre square of the OFT, indicating anxiogenic responses. Similarly, there was an interactive effect of footshocks and Aβ-42 lesion on: increased FK506 binding protein 51 (FKBP5) expression, which can be associated with stress-induced anxiogenic behaviours; and increased neuronal apoptosis in the PFC of the animals. In addition, footshocks, as well as Aβ-42 lesion, reduced superoxide dismutase levels and Bridging Integrator-1 (BIN1) expression in the PFC of the animals, which can be linked to the observed memory impairment. In conclusion, our findings indicate that footshocks exaggerate PFC-associated behavioural and molecular changes induced by an AD-like pathology., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that develops from exposure to trauma, mostly when normal psychological mechanisms fail. Studies have shown that people who have PTSD are susceptible to developing dementia, mostly Alzheimer's disease (AD), suggesting common underlying risk factors in the comorbidity. However, data elucidating links between these conditions is scarce. Here we show that footshock stress exacerbates AD-like pathology. To induce a trauma-like condition, the rats were exposed to multiple intense footshocks followed by a single reminder. This was followed by bilateral intrahippocampal lesions with amyloid-beta (Aβ) (1-42), to model AD-like pathology. We found that footshocks increased anxiety behavior and impaired fear memory extinction in Aβ(1-42) lesioned rats. We also found a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and an increased expression of Kelch-like ECH-associated protein 1 (Keap1) in the amygdala and hippocampus. Furthermore, oxidative stress level was sustained, which was associated with increased apoptosis in the amygdala and hippocampus. Our finding suggests that AD-like pathology can induce oxidative changes in the amygdala and hippocampus, which can be exaggerated by footshock stress., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dysregulation of inflammatory markers like cytokines is implicated in the pathophysiology of Alzheimer's disease (AD). Altered level of these cytokines show that pathogenesis of AD is beyond dysfunction of neurons resulting from amyloid beta accumulation but involves neuroinflammatory mechanisms elicited by the neuroimmune cell. In this study, we investigated the effect of amyloid-beta (1-42) (Aβ (1-42) ) on memory and how inflammatory markers respond to this model of AD. Male Sprague-Dawley rats were used for this study. The animals were randomly divided into four groups euthanized on day 3, 7, 10 and 14 post-lesion with amyloid-beta (5 μg/5 μl) while corresponding control groups were stereotaxically injected with a vehicle (5 μl of 0.01 M phosphate- buffered saline). The Morris water maze (MWM) test to access learning and memory was conducted pre and post-lesion and blood was collected through cardiac puncture on day 3, 7, 10 and 14 post lesion. Multiplex immunoassay was performed to determine the plasma levels of IL-1β, IL-6, IL-10 and TNF-α. Our results showed impaired spatial memory and elevated plasma levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) with a concomitantly lowered level of the anti-inflammatory cytokine (IL-10) in the Aβ (1-42) lesioned rats when compared to the vehicle groups. This study showed a negative correlation between the decline in performance of the spatial memory task and plasma levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and positive correlation with the anti-inflammatory cytokine IL-10. In conclusion, this study most importantly demonstrated an association between progressive decline in spatial memory and increased plasma cytokine level induced by the infusion of Aβ (1-42) ., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this case report, we describe a patient who remains in complete remission two years after the discontinuation of anti-EGFR monotherapy as a third-line treatment, accompanied by persistent severe hypomagnesemia. A 45-year-old Caucasian woman with mCRC started chemotherapy with weekly cetuximab. After ten months of treatment, the therapy was stopped because the patient had persistent grade III hypomagnesemia despite amiloride, oral, and intravenous magnesium. A month later, the patient was switched to panitumumab 6 mg/kg every two weeks for four additional months to avoid weekly visits to the clinic. Following discontinuation of panitumumab, PET scans remain negative to this day, two years after anti-EGFR therapy discontinuation. No factor has been identified to explain the complete and sustained response experienced by this patient. Hypomagnesemia is a common adverse effect of anti-EGFR therapy that can lead to treatment interruption and discontinuation if severe. This case highlights the importance of pursuing anti-EGFR therapy when a response is observed in spite of severe hypomagnesemia. It also provides preliminary information that anti-EGFR therapy could be stopped after a complete response is obtained.

Antisense-based molecules targeting HIV-1 RNA have the potential to be used as part of gene or drug therapy to treat HIV-1 infection. In this study, HIV-1 RNA was screened to identify more conserved and accessible target sites for ribozymes based on the hepatitis delta virus motif. Using a quantitative screen for effects on HIV-1 production, we identified a ribozyme targeting a highly conserved site in the Gag coding sequence with improved inhibitory potential compared to our previously described candidates targeting the overlapping Tat/Rev coding sequence. We also demonstrate that this target site is highly accessible to short hairpin directed RNA interference, suggesting that it may be available for the binding of antisense RNAs with different modes of action. We provide evidence that this target site is structurally conserved in diverse viral strains and that it is sufficiently different from the human transcriptome to limit off-target effects from antisense therapies. We also show that the modified hepatitis delta virus ribozyme is more sensitive to a mismatch in its target site compared to the short hairpin RNA. Overall, our results validate the potential of a new target site in HIV-1 RNA to be used for the development of antisense therapies.

41 patients with pemphigoid entered a multicentre randomised study of the efficacy of plasma exchange. All patients received 0.3 mg/kg daily oral prednisolone, increased weekly if the disease remained active. 24 patients received plasma exchanges in addition (eight large-volume exchanges over 4 weeks), and 17 had prednisolone only. 4 patients, 2 in each group, were withdrawn from the study. The initial dose of prednisolone was effective in 13 of 22 patients receiving plasma exchange but in none of 15 patients receiving prednisolone only. Control of the disease was obtained with a mean daily prednisolone dose of 0.52 +/- 0.28 mg/kg in the plasma exchange group v 0.97 +/- 0.33 mg/kg in the other group and a mean cumulative dose of 1240 +/- 728 mg v 2770 +/- 1600 mg. This finding suggests that plasma exchange allows a substantial saving of corticosteroids in the management of pemphigoid. This sparing effect was observed whether or not serum anti-basement membrane antibodies had been detected before treatment.