Studies examining the interplay between chronic pain, cognitive function, and functional brain abnormalities in older adults are scarce. To address this gap, we administered a series of neuropsychological tests and recorded electroencephalography (EEG) data during resting-state conditions in 26 older adults with chronic pain (CPOA), 30 pain-free older adults (OA), and 31 younger adults (YA). CPOA demonstrated poorer performance compared to OA on the Stroop test, the Wisconsin Card Sorting Test (WCST) and Digit Span. Both groups of older adults exhibited higher beta activity compared to younger adults, with CPOA displaying particularly elevated beta-2 activity localized in the posterior cingulate cortex compared to OA. Correlational analyses indicated that in CPOA participants, heightened beta activity was linked to decreased performance on the WCST. Conversely, in OA, we observed a positive correlation between beta activity and performance on the WCST. Overall, our findings suggest that the cumulative impact of pain in aging would diminish the effectiveness of the functional compensatory mechanisms that occur during healthy aging, exacerbating cognitive decline.
Coccidioidomycosis, commonly known as Valley fever, is an endemic fungal infection with a growing impact in the western United States. Patients with disseminated coccidioidomycosis (DCM) represent a rare and life-threatening subset of Valley fever who face years or a lifetime of antifungals to manage their disease. Immunocompromised patients with defective type 1 immunity or excessive type 2 immunity have an increased risk of dissemination. We previously published a single case employing the IL4/IL13 blocker dupilumab as an adjuvant to antifungal therapy. Here we present ten cases of patients in which adjuvant immunomodulation was provided for severe coccidioidomycosis. This is not an interventional trial. Cases were identified at UCLA by infectious disease experts in conjunction with immunology, and all subjects were deemed to be maximally treated with multiple conventional antifungals. Informed consent was obtained. We performed intracellular cytokine staining on CD4+ T cells and measured proportions of interferon gamma (IFN-γ), IL-4, and IL-17A–producing T cells. Treatment with IFN-γ was offered to those subjects showing life-threatening progression of disease despite maximal conventional care. Treatment with dupilumab was offered to those with excessive type-2 skewing. Clinical outcomes were assessed by laboratory studies, imaging results, and mycosis score. Our data follow 10 subjects for a median of 6 months after treatment. Our subjects showed excessive type 2-to-1 ratios, mostly due to excessive type 2 immune skewing and less often in subjects with poor type 1 responses. We found reduction of polyclonal type 2 responses in response to treatment with dupilumab. Clinical outcomes in all ten subjects were improved above the baseline state. Our work offers a new treatment employing immune modulation by cytokine blockade to treat a life-threatening infectious disease. Patients with poorly controlled disease may benefit from IFN-γ. Furthermore, subjects exhibiting a Th2-skewed response may benefit from dupilumab. Following the Casadevall damage–response framework, this tailored approach aligns immunomodulation with the underlying immunopathology. These observations provide evidence to support proper clinical trials of IFN-γ and dupilumab. Further research is needed to better characterize why cocci disseminates in certain subjects and which patients will benefit from immunomodulation.
The concept of pleasure in the Nicomachean Ethics change from book VII to X. I propose that such change in the definition of pleasure, and the place it takes in the Aristotelian corpus arise from how Aristotle uses the endoxic method. There are reasons to argue that the use of the method in Aristotle's Nicomachean Ethics, books VII and X, does not deal with a definition of pleasure, rather than the applicability of the concept of Activity ( en & eacute;rgeia ), for the sake of a metaphysical and political system. First, I render an interpretation about how the endoxic method is applied in NE. Second, I suggest that there is a discontinuity of how books VII and X define pleasure by the way of the concept of Activity is used. Third, the article concludes that the sudden change on the definition of pleasure is close to the objective of Aristotle's Politeia, that is, a sophistication of pleasure.
Increasing research points to a decline in the ability to internally regulate pain as a contributing factor to the increased pain susceptibility in aging. This study investigated the connection between pain regulation and resting-state functional connectivity (rsFC) in older adults with chronic pain. We compared functional magnetic resonance imaging rsFC of 30 older adults with chronic pain (69.5 ± 6.58 years, 14 males), 29 pain-free older (70.48 ± 4.60, 15 males), and 30 younger adults (20.0 ± 1.58, 15 males). Pain inhibition and facilitatory capabilities were assessed using conditioned pain modulation (CPM) and temporal summation. Older adults with chronic pain displayed lower pain inhibition during the CPM than pain-free older and younger adults. rsFC analysis showed that older adults with chronic pain, in comparison with younger participants, displayed an abnormal hyperconnectivity between right dorsolateral prefrontal cortex and left amygdala, which was significantly correlated with lower pain inhibition during the CPM. Older adults with chronic pain displayed higher connectivity between the primary somatosensory cortex and nucleus accumbens than pain-free older adults. Finally, both older adult groups displayed reduced connectivity between brain structures involved in pain inhibition and processing in comparison with younger adults. Altogether, our results suggest that suffering from pain during aging leads to a dysfunction of pain-inhibitory processes, which significantly surpass those caused by normal aging. Furthermore, our results point to a key role of emotional and motivational brain areas, and their interaction with executive and somatosensory areas, in the reduced inhibitory capacity and likely the maintenance of chronic pain in aging. PERSPECTIVE: This study examines the link between reduced pain-inhibition capacity and increased resting-state connectivity between affective, sensory, and executive brain structures in older adults with chronic pain. These findings could inform new pain assessment and treatment programs for this population.
