Search

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p

Osteoarthritis is characterized by enzymatic breakdown of the articular cartilage via the disruption of chondrocyte homeostasis, ultimately resulting in the destruction of the articular surface. Decades of research have highlighted the importance of inflammation in osteoarthritis progression, with inflammatory cytokines shifting resident chondrocytes into a pro-catabolic state. Inflammation can result in poor outcomes for cells implanted for cartilage regeneration. Therefore, a method to promote the growth of new cartilage and protect the implanted cells from the pro-inflammatory cytokines found in the joint space is required. In this study, we fabricate two gel types: polymer network hydrogels composed of chondroitin sulfate and hyaluronic acid, glycosaminoglycans (GAGs) known for their anti-inflammatory and prochondrogenic activity, and interpenetrating networks of GAGs and collagen I. Compared to a collagen-only hydrogel, which does not provide an anti-inflammatory stimulus, chondrocytes in GAG hydrogels result in reduced production of pro-inflammatory cytokines and enzymes as well as preservation of collagen II and aggrecan expression. Overall, GAG-based hydrogels have the potential to promote cartilage regeneration under pro-inflammatory conditions. Further, the data have implications for the use of GAGs to generally support tissue engineering in pro-inflammatory environments.

BACKGROUND: In Alzheimers disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo-MHC-IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.

CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

COVID-19 pandemic-related traumatic stress (PRTS) symptoms are reported in various populations, but risk factors in older adults with chronic medical conditions, remain understudied. We therefore examined correlates and pre-pandemic predictors of PRTS in older adults with hypertension during COVID-19. Participants in California, aged 61-92 years (n = 95), participated in a pre-pandemic healthy aging trial and later completed a COVID-19 assessment (May to September 2020). Those experiencing ⩾1 PRTS symptom (n = 40), and those without PRTS symptoms (n = 55), were compared. The PRTS+ group had poorer mental and general health and greater impairment in instrumental activities of daily living. Pre-pandemic biomarkers of vascular inflammation did not predict increased odds of PRTS; however, greater pre-pandemic anxiety and female gender did predict PRTS during COVID-19. Our findings highlight PRTS as a threat to healthy aging in older adults with hypertension; targeted approaches are needed to mitigate this burden, particularly for females and those with pre-existing anxiety.

PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p

Depression is known to be associated with inflammation among patients with established coronary heart disease (CHD), but it is unclear whether this is due to individual depression symptoms or to the broader construct of depression. We addressed this gap by using moderated non-linear factor analysis (MNLFA) to determine the extent that inflammation is associated with latent depression and/or individual symptoms in this patient group. We evaluated 1,024 outpatients with stable CHD from the baseline cross-sectional data of the Heart and Soul Study. Depression was assessed using the 9-item Patient Health Questionnaire, while inflammation was evaluated via C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels. MNLFA is based on the concept of model parameter moderation with regard to individual characteristics. Using the MNLFA approach, we simultaneously tested for differences in (1) latent depression, (2) individual depression items, and (3) the factor loading of the item on latent depression as a function of inflammatory markers, with and without covariate adjustment. Higher TNF-α levels were associated with both higher levels of a latent depression factor and greater endorsement of an individual symptom (appetite changes). Increased CRP levels were significantly associated with greater appetite changes, lower concentration difficulty, and greater fatigue. Elevated IL-6 levels were only related to greater fatigue, while increased MCP-1 levels were linked to greater sleep disturbance. After adjusting for covariates, some associations became insignificant. Inflammatory markers were not consistent predictors of factor loadings. This study represents the initial step to discussing how inflammation biology is truly related to depression among patients with established CHD.

Purpose: To review experimental peri-implantitis studies using rat models and summarize different peri-implantitis induction techniques and evaluate their effectiveness. Materials and Methods: Electronic searches were conducted by two independent examiners to address the following issues. Meta-analyses explored the marginal bone loss (MBL) of four types of peri-implantitis induction methods in rats. The detailed induction tactics--such as the implant design, implant size, surgical process, time cost, induction methods, and endpoint measurements--were summarized. Results: Of the 18 included studies, 38.9% of the studies placed implants at the maxillary first molar, and 44.4% placed them at the alveolar ridge region anterior to the maxillary first molar. As for the induction method, the numbers of published studies on ligature methods, bacterial inoculation, and bacterial lipopolysaccharide inoculation were equally high among all selected studies. The total implant survival rate at the end was 160 out of 213 implants (75.11%). Eight studies with high pooled heterogeneity (I2 = 98, P < .01) in the meta-analysis reported an overall MBL (µ-CT) of 0.47 mm (95% CI = 0.14 to 0.81). A subgroup analysis estimated an MBL of 0.31 mm (95% CI = 0.12 to 0.50) for bacterial inoculation and 0.66 mm (95% CI = 0.07 to 1.26) for the ligature method. Histopathologic analysis revealed that peri-implantitis in rats was similar to peri-implantitis lesions in humans. Conclusions: Implant placement at the maxillary first molar with bacterial inoculation and the silk ligature method to build peri-implantitis rat models is reliable to use for research on peri-implantitis. [ABSTRACT FROM AUTHOR]

Purpose: To assess the pain, swelling, infection, and alteration in sensation following the flapless placement of zygomatic implants guided by dynamic navigation. Materials and Methods: A randomized controlled trial was conducted on 20 patients. In group 1, the placement of the zygomatic implants was carried out without reflecting a mucoperiosteal flap (flapless). In group 2, a mucoperiosteal flap was raised (flapped). Two zygomatic implants were placed in each patient (one on each side) under local anesthesia, guided by dynamic navigation. Postoperative evaluations included pain (using the visual analogue scale [VAS]), swelling (using standard measurements), maxillary sinus infection, and alteration of sensation (using mechanical stimuli, thermal threshold detection, and a two-point discrimination test). The assessments were carried out at 2 days, 1 week, and then 1, 2, and 3 months postoperatively. Results: In group 1, all implants except for one were successfully osseointegrated. Immediate postoperative pain and swelling were both significantly greater in group 2 (P < .01). No alteration in sensation was detected in any case in the two groups. There were a total of three cases of chronic sinusitis: one in group 1 and two in group 2. Conclusions: The flapless placement of zygomatic implants guided by dynamic navigation and under local anesthesia improves postoperative recovery. [ABSTRACT FROM AUTHOR]

Objective: Inflammatory pathogenesis is common to periodontitis and oral lichen planus. This study was conducted to assess and compare the periodontal status of patients with and without oral lichen planus. Method and materials: 108 patients comprising 54 with oral lichen planus and 54 age-matched systemically healthy participants without oral lichen planus were selected. Periodontal parameters, ie Plaque Index, Gingival Index, bleeding on probing, probing pocket depth, clinical attachment level, and periodontal phenotype were measured. Results: On comparing the test and control groups, statistically significant differences were observed in respect to Plaque Index (P = .00), Gingival Index (P = .00), and bleeding on probing (P = .00). A higher proportion of sites with deeper pockets was observed in the test group (P = .00). On comparison of various oral lichen planus subtypes, significant difference was observed in respect to Gingival Index (P = .00) and bleeding on probing (P = .00). A higher proportion of sites with deeper pockets (P = .01) and greater CAL (P = .00) was observed in the erosive/atrophic subgroup compared to the reticular group. However, the differences between the reticular (a less severe form of oral lichen planus) and control group in terms of Gingival Index (P = .94), Plaque Index (P = .05), bleeding on probing (P = .17), probing pocket depth (P = .56), and clinical attachment level (P = .23) were not statistically significant. Statistically significant differences were observed in terms of Gingival Index (P = .01) and bleeding on probing (P = .00) between thin and thick periodontal phenotypes in the oral lichen planus group. Statistically significant positive correlations in periodontal parameters with increased gingival involvement and severity were observed using Spearman rank correlation coefficient. Conclusion: Significantly greater periodontal inflammation in the test group means there is a risk of greater attachment loss in future. Thus, increased attention towards periodontal health in these patients might reduce the rate of disease progression. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the process of early oral osseointegration of titanium (Ti) implants in diabetic 129/Sv mice through microCT and histologic and immunohistochemical analysis. Materials and Methods: A group of 30 male 129/Sv mice was equally subdivided into two groups: (1) nondiabetic (ND), in which mice did not undergo systemic alterations and received a standard diet, and (2) diabetic (D), in which mice were provided a high-fat diet from the age of 6 weeks until the conclusion of the study and received two intraperitoneal (IP) injections of streptozotocin (STZ) at a concentration of 100 mg/Kg each. Each mouse underwent extraction of a maxillary first molar, and customized Ti screws (0.50 mm diameter, 1.5 mm length) were placed in the residual alveolar sockets of the palatal roots. At 7 and 21 days after implant placement, the animals were euthanized for maxilla and pancreas collection. Maxillae containing Ti implants were analyzed with microCT, histology, and immunohistochemistry for cells that were positive for F4/80, CD146, runt-related transcription factor 2 (Runx2), and proliferating cell nuclear antigen (PCNA). Pancreata were histologically analyzed. Quantitative data were statistically analyzed with a significance level at 5% (P < .05). Results: ND mice presented successful healing and osseointegration, with a significantly higher fraction of bone volume compared to D mice, both at the alveolar sockets (53.39 ± 5.93 and 46.08 ± 3.18, respectively) and at the implant sites (68.88 ± 7.07 and 44.40 ± 6.98, respectively) 21 days after implant placement. Histologic evaluation revealed that the ND mice showed a significant decrease in inflammatory infiltrate and a significant increase in newly formed bone matrix at 21 days, whereas peri-implant sites in the D mice were predominantly encapsulated by fibrous tissue and chronic inflammatory infiltrate. Immunohistochemical characterization revealed higher Runx2 osteoblast differentiation and higher cell proliferation activity in the ND mice at 7 days, while higher amounts of macrophages were present in D mice at 7 and 21 days. Interestingly, no differences were found in CD146-positive cells when comparing ND and D mice. Conclusions: This study evaluated the effects of immediate dental implant placement in 129/Sv diabetic mice by using specific healing markers to identify changes in cellular events involved in early oral osseointegration. This approach may serve as tool to evaluate new materials and surface coatings to improve osseointegration in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Children with inflammatory bowel disease (IBD) experience extraintestinal side effects including altered body composition, impaired muscle strength, and aerobic capacity. Exercise training may remedy these issues. Purpose: To assess the feasibility, safety, participant satisfaction, and efficacy of a training program for youth with IBD. Methods: Children with IBD completed 16 weeks of training (2 supervised + 1 home sessions per week). Feasibility was assessed by tracking recruitment, adherence, and compliance rates. Safety was assessed by tracking symptoms and adverse events. Posttraining interviews gauged satisfaction. Circulating inflammatory markers, body composition, muscle strength, aerobic fitness, and habitual physical activity were measured at baseline, midtraining (8 wk), and posttraining. Results: Eleven youth were recruited and 10 completed the study. Participants adhered to 28 (1) of 32 prescribed supervised sessions and 8 (4) of 16 prescribed home sessions. There were no adverse events, and overall feedback on training was positive. Posttraining, we observed an increase in lean mass (+2.4 [1.1] kg), bone density (+0.0124 [0.015] g·cm−2), aerobic fitness (+2.8 [5.7] mL·kg LM−1· min−1), and vigorous physical activity levels (+13.09 [8.95] min·h−1) but no change in inflammation or muscle strength. Conclusion: Supervised exercise training is feasible, safe, and effective for youth with IBD and should be encouraged. [ABSTRACT FROM AUTHOR]