Charlie Norwood VA Medical Center

Decades of experimental and clinical data revealed that spreading depolarizations (SDs) play a central causal role in the development of cortical lesions after acute brain injury. However, clinical documentation of events at the onset of focal ischemic stroke and during the initial phase of cortical injury development is lacking because electroencephalography monitoring of SD typically starts hours or days later. Here, we used nonhuman primates to map electrophysiological pathology through focal ischemic stroke's onset and acute stage. Craniotomies were performed over both hemispheres on 4 male and 1 female nemestrina and rhesus macaques aged 23 years to 32 years. Subdural electrode arrays were placed bilaterally over the middle cerebral artery territory, recording from 24 electrodes 1 cm apart on the left cortex and 7 on the right. After 30 minutes of baseline monitoring, the left middle cerebral artery and, in some cases, also the left internal carotid or anterior cerebral arteries were permanently occluded with aneurysmal clips. Repetitive SDs occurred during the next 3 hours, followed by terminal SD during euthanasia. No epileptiform activity was observed in any of the 5 animals. Nonspreading electrical silence developed in the ischemic core within seconds of ischemic onset, followed by terminal SD and SD-initiated negative ultraslow potential after several minutes. These events defined the ischemic core and led to histologically confirmed cell damage. Initial and subsequent transient SDs caused spreading depression of spontaneous activity in the normally perfused surrounding cortex without any signs of histological damage. Cardiocirculatory arrest at the end of experiments first induced nonspreading depression of activity followed by SD and, eventually, the SD-initiated negative ultraslow potential, which indicated brain death. Results in gyrencephalic nonhuman primates hold significant implications for understanding the role of SD in acute brain injury development and for the clinical translation and diagnosis of pathologies manifested in the SD continuum.

There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals. There have been several efforts to characterize these youthful or maturation-associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age-dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti-inflammatory, and reduced cellular senescence markers. MicroRNA sequencing of the EVs showed an age-associated signature and identified miR-296-5p and miR-541-5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR-296-5p and miR-541-5p showed a reparatory effect in an in vitro wound healing model and the miR-296-5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis. In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation-dependent. Our observation that miR-296-5p and miR-541-5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these miRNAs in inflammation and age-associated diseases.

With the growing interest in urology, it is increasingly important and useful to understand the factors that attract urology residency applicants to programs. We sought to investigate the impact of social media and other program-related characteristics on the application rates of urology residency programs. Match cycle data for 2019-2022 was collected for 140 accredited urology residency programs in the United States. The associations between the number of applicants, program social media presence and activity, Doximity rankings, program size, city population, and city quality of life were assessed. Multivariate analyses were conducted. Programs with Twitter/X, Facebook, and YouTube had significantly more applicants than those without (p < 0.05). There was a significant positive correlation between application rates and activity metrics on Twitter/X but not on other platforms (p < 0.05). Programs with more residents and higher reputation rankings received more applications from 2019 to 2022, including in the multivariate model (p < 0.05). Programs in cities with larger populations, but not better city quality of life rankings, received significantly more applicants from 2019 to 2022 (p < 0.0001). Programs should prioritize the use of Twitter/X to enhance their visibility, showcase their strengths, and connect with applicants. Reputation rankings and program size have the greatest effect on application rates, while city population and overall social media presence also play important roles. Residency programs can leverage these insights to enhance their appeal to potential applicants who might be the best "fit".

The social deficits following chronic stress conditions are linked to synaptic dysfunction in the brain. Complement system plays a critical role in synapse regulation. Although complement has been implicated in chronic stress-induced behavior deficits the cellular substrates and mechanisms underlying complement-mediated behavior changes under chronic stress conditions are not known. In the present study, we investigated the role of complement component 3a receptor (C3ar1) in microglia and monocytes/macrophages (Mo/MΦ) in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found that deletion of microglial C3ar1 attenuated stress-induced social behavior deficits and changes in neuroinflammatory as well as synaptic markers in the prefrontal cortex (PFC). RNA sequencing data revealed that microglial C3ar1 deletion attenuates CUS-mediated changes in the expression of immediate-early genes such as Fos and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. In contrast, lack of C3ar1 in Mo/MΦ induced social behavior deficits. Together, these findings indicate opposite functions of C3ar1 signaling in microglia and Mo/MΦ under chronic stress conditions.

Diabetic retinopathy, a major cause of vision loss, is characterized by neurovascular changes in the retina. The lack of effective treatments to preserve vision in diabetic patients remains a significant challenge. A previous study from our laboratory demonstrated that 12-week treatment with MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX, a critical regulator of polyamine metabolism), reduced neurodegeneration in diabetic mice. Utilizing the streptozotocin-induced diabetic mouse model and MDL 72527, the current study investigated the effectiveness of SMOX inhibition on the measures of vision impairment and neuro-glial injury following 24 weeks of diabetes. Reductions in visual acuity, contrast sensitivity, and inner retinal function in diabetic mice were improved by MDL 72527 treatment. Diabetes-induced changes in neuronal-specific class III tubulin (Tuj-1), synaptophysin, glutamine synthetase, and vimentin were attenuated in response to SMOX inhibition. In conclusion, our findings show that SMOX inhibition improved visual acuity, contrast sensitivity, and inner retinal function and mitigated diabetes-induced neuroglial damage during long-term diabetes. Targeting SMOX signaling may provide a potential strategy for reducing retinal neuronal damage and preserving vision in diabetes.

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.

The molecular basis of renal interstitial fibrosis, a major pathological feature of progressive kidney diseases, remains poorly understood. Autophagy has been implicated in renal fibrosis, but whether it promotes or inhibits fibrosis remains controversial. Moreover, it is unclear how autophagy is activated and sustained in renal fibrosis. The present study was designed to address these questions using the in vivo mouse model of unilateral ureteral obstruction and the in vitro model of hypoxia in renal tubular cells. Both models showed the activation of hypoxia-inducible factor-1 (HIF-1) and autophagy along with fibrotic changes. Inhibition of autophagy with chloroquine reduced renal fibrosis in unilateral ureteral obstruction model, whereas chloroquine and autophagy-related gene 7 knockdown decreased fibrotic changes in cultured renal proximal tubular cells, supporting a profibrotic role of autophagy. Notably, pharmacological and genetic inhibition of HIF-1 led to the suppression of autophagy and renal fibrosis in these models. Mechanistically, knock down of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a downstream target gene of HIF, decreased autophagy and fibrotic changes during hypoxia in BUMPT cells. Together, these results suggest that HIF-1 may activate autophagy via BNIP3 in renal tubular cells to facilitate the development of renal interstitial fibrosis.NEW & NOTEWORTHY Autophagy has been reported to participate in renal fibrosis, but its role and underlying activation mechanism is unclear. In this study, we report the role of HIF-1 in autophagy activation in models of renal fibrosis and further investigate the underlying mechanism.

Deep neck space infections (DNSI) are severe infections within the layers of neck fascia that are known to be associated with underlying immunocompromised states. Although uremia associated with kidney disease is known to cause immune system dysfunction, DNSI in patients with kidney disease has been poorly studied. This study investigated the prevalence of DNSI and the associated risk of mortality within the United States end-stage renal disease (ESRD) population, using a retrospective cohort study design and the United States Renal Data System database of patients (ages 18-100) who initiated dialysis therapy between 2005 and 2019. International Classification of Disease-9 and -10 codes were used to identify the diagnosis of DNSI and comorbid conditions. Of the 705,891 included patients, 2.2% had a diagnosis of DNSI. Variables associated with increased risk of DNSI were female sex, black compared to white race, catheter, or graft compared to arteriovenous fistula (AVF) access, autoimmune disease, chronic tonsillitis, diagnoses in the Charlson Comorbidity Index (CCI), tobacco use, and alcohol dependence. DNSI diagnosis was an independent risk factor for mortality, which was also associated with other comorbidity factors such as older age, catheter or graft compared to AVF access, comorbidities in the CCI, tobacco use, and alcohol dependence. Because of the increased mortality risk of DSNI in the ESRD population, health professionals should encourage good oral hygiene practices and smoking cessation, and they should closely monitor these patients to reduce poor outcomes.