Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD+ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD+ synthesis by limiting the conversion of downstream quinolinate to NAD+, a profile recapitulated in aging macrophages. Increasing de novo NAD+ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD+ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD+ synthesis may underlie declining NAD+ levels and rising innate immune dysfunction in aging and age-associated diseases.
IMPORTANCE Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia. OBJECTIVE To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants. MAIN OUTCOMES AND MEASURESUsing atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem.An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants. RESULTSThis study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F 21,74 = 6.91; P < .001; partial η 2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow. (continued) Key Points Question How does diffusion-weighted magnetic resonance imaging differ between patients with pediatric acuteonset neuropsychiatric syndrome and pediatric control participants? Findings In this case-control study of 34 consecutive patients with pediatric acute-onset neuropsychiatric syndrome who had 3 Tesla magnetic resonance imaging, all assessed brain regions, particularly the deep gray matter (eg, the thalamus, b...
often group Native Hawaiian and Other Pacific Islander individuals together with Asian individuals despite being consistently identified as having worse health outcomes and higher rates of comorbidities and mortality. Native Hawaiian and Other Pacific Islander individuals also have high incidence rates of oral cavity and pharyngeal cancer compared with the general population; however, disparities in clinical presentation and survival outcomes of head and neck cancer squamous cell carcinoma (HNSCC) among this population have not been investigated nor compared with those of other races. OBJECTIVE To determine the association of race with cancer stage at diagnosis and survival outcomes among Native Hawaiian and Other Pacific Islander patients with HNSCC compared with Asian and non-Hispanic White patients. DESIGN, SETTING, AND PARTICIPANTS This was a retrospective population-based cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Asian, Native Hawaiian or Other Pacific Islander, and non-Hispanic White adult patients diagnosed in 1988 through 2015 with HNSCC of the oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx were included; any patient whose record was missing data on disease or demographic information was excluded. MAIN OUTCOMES AND MEASURES Cancer stage at presentation was compared among Asian, Native Hawaiian and Other Pacific Islander, and non-Hispanic White patients using a multivariable logistic regression model. Survival outcomes were compared among these racial groups using Cox regression models. Data analyses were performed from July 1, 2021, to March 20, 2022. RESULTS The total study population comprised 76 473 patients: 4894 Asian (mean [SD] age at presentation, 60.7 [14.6] years), 469 Native Hawaiian and Other Pacific Islander (57.8 [12.3] years), and 71 110 non-Hispanic White (62.2 [12.1] years) individuals. Native Hawaiian and Other Pacific Islander patients were more likely to present with advanced-stage HNSCC (odds ratio [OR], 1.38; 95% CI, 1.12 -1.72) compared with non-Hispanic White patients. Asian patients presented with similar stage disease (OR, 1.04; 95% CI, 0.97-1.11) compared with non-Hispanic White patients. Native Hawaiian and Other Pacific Islander patients had worse disease-specific survival (HR, 1.18; 95% CI, 1.02-1.36) compared with non-Hispanic White patients after adjusting for clinical and demographic factors. In contrast, Asian patients had improved disease-specific survival (HR, 0.93; 95% CI, 0.88-0.98) compared with non-Hispanic White patients.CONCLUSIONS AND RELEVANCE This retrospective population-based cohort study suggests that Native Hawaiian and Other Pacific Islander race was associated with more advanced HNSCC, and worse disease-specific survival compared with non-Hispanic White race, while Asian race was associated with improved survival. This study highlights the importance of disaggregating Asian from Pacific Islander data when assessing health disparities, and the need for culturally sensitive interventions t...
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