Exploring the impact of therapeutic advances in HIV-related mortality in the United States.

Objectives: Mortality from HIV has significantly declined with the introduction of highly active antiretroviral therapy (HAART). This study sought to examine the longitudinal trends in mortality from HIV-related diseases by race, sex, geographical region, and over time as HAART trends changed. Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database and performed serial cross-sectional analyses of national death certificate data for all-cause mortality with comorbid HIV from 1999 to 2020. HIV diseases (International Classification of Diseases, Tenth Revision codes B20-B24, O98.7, R75) were listed as the contributing cause of death. We calculated the age-adjusted mortality ratio (AAMR) per 1,000,000 individuals and determined mortality trends using the Joinpoint Regression Program. Subgroup analyses were performed by sex, race, region, and organ system. The study period was further stratified into three groups when specific drug regimens were more prevalent. Results: In the 22-year study period, 251,759 all-cause mortalities with comorbid HIV were identified. The leading cause of death was infectious disease (84.0%, N = 211,438). Men recorded a higher AAMR than women (4.66 vs 1.65, P < 0.01). African American individuals had the highest AAMR (13.46) compared to White, American Indian, and Asian individuals (1.70 vs 1.65 vs 0.47). The South region had the highest AAMR (4.32) and urban areas had a higher AAMR compared to rural areas (1.77 vs 0.88). Conclusions: More than 80% of deaths occurred because of infectious disease over the last 2 decades with a decreasing trend over time when stratified by race, sex, and geographical region. Despite advances in HAART, mortality disparities persist which emphasizes the need for targeted interventions in these populations.

Gut microbiota and their metabolite profiles following peripheral nerve xenotransplantation.

Background: Intestinal pathogens are associated with xenotransplantation tolerance and rejection. However, changes in the gut microbiota in patients who have undergone peripheral nerve xenotransplantation and their association with immune rejection have not yet been reported. Objective: We aimed to explore intestinal microbes and their metabolites at different time points after peripheral nerve transplantation to provide new insight into improving transplant tolerance. Methods: A peripheral nerve xenotransplantation model was constructed by suturing the segmented nerves of Sprague Dawley rats to those of C57 male mice using xenotransplantation nerve bridging. Fecal samples and intestinal contents were collected at three time points: before surgery (Pre group; n = 10), 1 month after transplantation (Pos1 m group; n = 10), and 3 months after transplantation (Pos3 m group; n = 10) for 16S DNA sequencing and nontargeted metabolome detection. Results: Alpha diversity results suggested that species diversity was significantly downregulated after peripheral nerve xenotransplantation. There were six gut flora genera with significantly different expression levels after xenotransplantation: four were downregulated and two were upregulated. A comparison of the Pre vs. Pos1 m groups and the Pos1 m vs. Pos3 m groups revealed that the most significant differentially expressed Kyoto Encyclopedia of Genes and Genomes metabolite pathways were involved in phenylalanine, tyrosine, and tryptophan biosynthesis, as well as histidine metabolism. Metabolites with a strong relationship to the differentially expressed microbial flora were identified. Conclusion: Our study found lower gut microbiome diversity, with increased short-chain fatty acid (SCFA)-producing and sulfate-reducing bacteria at 1 month post peripheral nerve xenotransplantation, and these were decreased at 3 months post-transplantation. The identification of specific bacterial metabolites is essential for recognizing potential diagnostic markers of xenotransplantation rejection or characterizing therapeutic targets to prevent post-transplant infection.

Interleukin 37's role in promoting nerve repair and attenuating immune rejection of peripheral nerve xenografts in mice.

Background The aim of the study was to explore the potential role of IL-37 in nerve repair and immune regulation in peripheral nerve xenograft hosts. Methods Rat nerve xenografts were transplanted into mouse recipients. Transplanted mice received an intraperitoneal injection of IL-37 on the day before transplantation, whereas control mice remained untreated. At postoperative 2, 4, 8, and 12 weeks, the effects of IL-37 were examined on motor function, tissue morphology, and regenerative ability of xenograft nerves. Levels of IL-17 and IL-22 in serum and spleen were measured at 3, 7, 14, and 28 days after nerve transplantation. Results At 12 postoperative weeks, grafted nerves grew well in IL-37 treatment group, as documented by the recovery in function of sciatic nerves compared to untreated controls. In particular, IL-37-treated mice showed more complete neuromorphology, thicker myelin sheath, compact structure, and the increased number of myelinated nerve fibers in histological examination. The number of T helper (Th)17 (CD3 + CD4 + IL-17+) and Th22 (CD3 + CD4 + IL-22+) cells in the spleen was reduced in the IL-37-treated group, as well as serum IL-17 and IL-22 were decreased after IL-37 treatment compared with the untreated group. Conclusions IL-37 attenuates immunomodulatory responses induced by xenografts, contributing to the recovery of nerve function and the prevention of muscle atrophy caused by nerve grafts.

The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice.

Depression is increasingly recognized as an inflammatory disease, with inflammatory crosstalk in the brain contributing its pathogenesis. Life stresses may up-regulate inflammatory processes and promote depression. Although cytokines are central to stress-related immune responses, their contribution to stress-induced depression remains unclear. Here, we used unpredictable chronic mild stress (UCMS) to induce depression-like behaviors in mice, as assessed through a suite of behavioral tests. C-X-C motif chemokine ligand 1 (CXCL1)-related molecular networks responsible for depression-like behaviors were assessed through intrahippocampal microinjection of lenti-CXCL1, the antidepressant fluoxetine, the C-X-C motif chemokine receptor 2 (CXCR2) inhibitor SB265610, and the glycogen synthase kinase-3ß (GSK3ß) inhibitor AR-A014418. Modulation of apoptosis-related pathways and neuronal plasticity were assessed via quantification of cleaved caspase-3, B-cell lymphoma 2-associated X protein, cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) protein expression. CXCL1/CXCL2 expression was correlated with depression-like behaviors in response to chronic stress or antidepressant treatment in the UCMS depression model. Intrahippocampal microinjection of lenti-CXCL1 increased depression-like behaviors, activated GSK3ß, increased apoptosis pathways, suppressed CREB activation, and decreased BDNF. Administration of the selective GSK3ß inhibitor AR-A014418 abolished the effects of lenti-CXCL1, and the CXCR2 inhibitor SB265610 prevented chronic stress-induced depression-like behaviors, inhibited GSK3ß activity, blocked apoptosis pathways, and restored BDNF expression. The CXCL1/CXCR2 axis appears to play a critical role in stress-induced depression, and CXCR2 is a potential novel therapeutic target for patients with depression.-Chai, H.-H., Fu, X.-C., Ma, L., Sun, H.-T., Chen, G.-Z., Song, M.-Y., Chen, W.-X., Chen, Y.-S., Tan, M.-X., Guo, Y.-W., Li, S.-P. The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice.