Residual Inflammation Research Articles

A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity.

Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, Alzheimer's disease pathophysiology has focused on two culprits, amyloid-β induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This is confounded by data showing amyloid-β to be an endogenous antimicrobial that is increased in a wide array of diverse medical conditions associated with heightened inflammation. This article reviews the wider bodies of data pertaining to Alzheimer's disease pathophysiology, highlighting the role of suppressed astrocyte mitochondrial function and mitochondrial melatonergic pathway as a core hub in driving neuronal loss in dementia. It is proposed that astrocyte function over aging becomes dysregulated, at least partly mediated by systemic processes involving the 10-fold decrease in pineal melatonin leading to the attenuated capacity of night-time melatonin to dampen residual daytime inflammation. Suppressed pineal melatonin also attenuates melatonin's inhibition of glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but also the consequences of the cortisol awakening response, which 'primes the body for the coming day'. Gut microbiome-derived butyrate also inhibits glucocorticoid receptor nuclear translocation, as well as inducing the mitochondrial melatonergic pathway. It is proposed that the loss of astrocyte melatonin prevents the autocrine and paracrine effects of melatonin in limiting amyloid-β levels and effects. Suppressed astrocyte melatonin production also attenuates the melatonin induction of astrocyte lactate, thereby decreasing neuronal mitochondrial metabolism and the neuronal mitochondrial melatonergic pathway. The loss of astrocyte lactate and melatonin, coupled to the suppression of neuronal mitochondrial metabolism and melatonin production decreases mitophagy, leading to the induction of the major histocompatibility complex (MHC)-1. MHC-1 initiates the chemoattraction of CD8+ t cells, leading to neuronal destruction in Alzheimer's disease being driven by 'autoimmune'/'immune-mediated' processes. Alzheimer's disease may therefore be conceptualized as being initiated by systemic processes that act on astrocytes as a core hub, with the suppression of the astrocyte melatonergic pathway leaving neurons deplete of appropriate metabolic substrates and co-ordinated antioxidants. This culminates in an 'immune-mediated' cell death. Future research and treatment/prevention implications are indicated.

Bibliometric analysis of residual cardiovascular risk: trends and frontiers.

The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.

Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury

BackgroundRhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown. MethodsRhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation. FindingsFn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis. InterpretationTWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury. FundingSpanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.

Computed tomography plaque analysis identifies residual inflammation in recent acute myocardial infarction patients

Abstract Introduction Residual inflammatory risk (RIR) following acute myocardial infarction (AMI) patients is associated with recurrent major adverse cardiovascular events. Atherosclerotic plaque quantification using computed tomographic coronary angiography (CTCA) can specifically identify inflamed plaque characteristics. We compared plaque burden and tissue composition in AMI patients with those of stable coronary artery disease (CAD) patients to identify imaging markers of RIR. Purpose We aimed to identify signs of residual inflammation in recent AMI patients via CTCA atheroma quantification. We hypothesised that recent AMI patients have plaque characteristics suggestive of inflammation. Methods 108 patients recruited from multiple sites with AMI <1 month were propensity-matched via CAD risk factors (age, gender, diabetes, hypertension, hyperlipidaemia, smoking and family history of CAD) with stable CAD patients in a 1:1 ratio. Propensity matched recent AMI and stable CAD patient cohorts had similar profiles: age (60±9.7 vs 57±10.0 years), gender (91.7% vs 92.6% male), diabetes (13.9% vs 15.7%), hypertension (44.4% vs 50.9%) and hyperlipidaemia (50.9% vs 63.9%, p>0.05 for all). Total plaque burden (total lesion volume/total vessel volume) and plaque composition (fibrous fatty [fibrofatty, FF, 31 – 130 HU], necrotic core [NC, -30 – 30 HU], fibrous [131 – 350 HU] and calcium [> 350 HU]) were extracted from CTCA scans and aggregated per patient. Culprit lesions of recent AMI patients were excluded from the analysis due to the fact that coronary stents would affect plaque characterisation. Multivariate linear regression, corrected for CAD risk factors, was used to compare these parameters between the two cohorts. Results Recent AMI patients and stable CAD patients had similar total plaque burden (β=0.001±0.013, p=0.950, Figure 1a). Patients with recent AMI had higher non-calcified plaque volume ratio (β=0.071±0.026, p<0.05, Figure 1b) due to higher FF (β=0.094±0.019, Figure 1d) and NC (β=0.025 ± 0.005, Figure 1e) plaque volume (p<0.05 for all), but less fibrous plaque volume (β = -0.048±0.019, p<0.05, Figure 1c). Conclusions Recent AMI patients had a greater non-calcified plaque burden than stable CAD patients due to larger FF and NC plaque burden. Since FF and NC components indicate ongoing inflammation in the plaque, while fibrous content indicates resolved inflammation; increased NC and FF burden suggest increased coronary plaque inflammation in non-culprit lesions of recent AMI patients, supporting the presence of residual inflammation in recent AMI patients.Figure 1

Evaluating the effect of the antiPCSK9 vaccine on systemic inflammation and oxidative stress in CFA-challenged albino mice

Abstract Background Besides effective lipid lowering therapy aimed to reduce LDL-C, one should always look at other risk factors that may essentially increase the risk of residual cardiovascular disease risk, including diabetes, thrombotic factors and inflammation. Purpose To find whether the antiPCSK9 vaccine can affect the serum C-reactive protein (CRP) and oxidative stress during acute systemic inflammation. Methods Male albino mice were randomly divided into three groups, including non-treated mice (the sham group), mice treated with Freund's complete adjuvant (CFA) (the CFA group), and vaccinated mice treated with CFA (the vaccine group). The vaccine group was subcutaneously immunized with the antiPCSK9 formulation, four times in bi-weekly intervals. To induce inflammation, all mice were subjected to the CFA challenge after the vaccination plan. To determine the efficacy of the antiPCSK9 vaccine in albino mice, plasma antiPCSK9 antibody titer, plasma PCSK9 concentration, and PCSK9/LDLR interaction were assayed. The serum level of high-sensitive CRP (hs-CRP) and oxidative stress status were evaluated by a mouse CRP ELISA kit and the pro-oxidant antioxidant balance (PAB) assay, respectively. Results Upon three boosters, the vaccine induced a high-titer IgG antiPCSK9 antibody in albino mice, which was accompanied with a significant reduction in the plasma level of the free PCSK9 (-24.7% and -28.5% compared with the sham and CFA group, respectively), and the inhibition of PCSK9/LDLR interaction (-27.8% and -29.4% compared with the sham and CFA group, respectively). In addition, the serum level of hs-CRP was significantly increased in the vaccine and CFA groups by 225% and 274%, respectively, when compared with the sham group; however, it was non-significantly decreased (-18%) in the vaccine group in comparison with the CFA group (Figure 1A). Moreover, the PAB values indicated that oxidative stress was significantly increased in the CFA group (by 72.7%) and the vaccine group (by 76%) when compared to the sham group; however, there was no significant difference in the PAB values between the vaccine and CFA groups (Figure 1B). Conclusion Our results indicate that, despite inducing the production of the functional antiPCSK9 antibodies, the antiPCSK9 vaccine failed to significantly reduce the serum hs-CRP and oxidative stress induced in the CFA-challenged albino mice. Figure 1. The effect of the antiPCSK9 vaccine on (A) the serum level of hs-CRP in albino mice and (B) the serum PAB in albino mice. The sham group involved non-treated mice, the CFA group involved the CFA-treated mice, and the vaccine group involved mice who after vaccination were treated with the CFA. Pooling of samples was performed to obtain sufficient sample volume for assay, when needed. The PAB values were expressed in an arbitrary HK (Hamidi-Koliakos). Data are expressed as mean ±SD (10 mice per group). Statistical differences at a p-value <0.05 were considered as significant.Figure 1.

Abstract 13695: Finerenone Added to RAS/SGLT2 Blockade for Non-Diabetic Chronic Kidney Disease. Results of a Preclinical Double-Blinded Randomized Controlled Trial

Introduction: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or plus the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. Hypothesis: We hypothesized that triple therapy with a combination of RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression Methods: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3-deficient mice with established Alport nephropathy. Treatment was initiated late (6 weeks of age) in mice with elevated serum creatinine and albuminuria and in presence of glomerulosclerosis, interstitial fibrosis and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary endpoint was mean survival. Results: Mean survival was 63.7 ± 10.0 days (vehicle), 77.3 ± 5.3 days (ramipril), 80.3 ± 11.0 days (dual), and 103.1 ± 20.3 days (triple), respectively. Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. Conclusions: This preclinical randomized controlled trial suggests that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive chronic kidney disorders for synergistic effects on the glomerular and tubulointerstitial compartment, respectively.

Osseointegration of functionally graded Ti6Al4V porous implants: Histology of the pore network

The additive manufacturing of titanium into porous geometries offers a means to generate low-stiffness endosseous implants with a greater surface area available for osseointegration. In this work, selective laser melting was used to produce gyroid-based scaffolds with a uniform pore size of 300 μm or functionally graded pore size from 600 μm to 300 μm. Initial in vitro assessment with Saos-2 cells showed favourable cell proliferation at pore sizes of 300 and 600 μm. Following implantation into rabbit tibiae, early histological observations at four weeks indicated some residual inflammation alongside neovessel infiltration into the scaffold interior and some early apposition of mineralized bone tissue. At twelve weeks, both scaffolds were filled with a mixture of adipocyte-rich marrow, micro-capillaries, and mineralized bone tissue. X-ray microcomputed tomography showed a higher bone volume fraction (BV/TV) and percentage of bone-implant contact (BIC) in the implants with 300 μm pores than in the functionally graded specimens. In functionally graded specimens, localized BV/TV measurement was observed to be higher in the innermost region containing smaller pores (estimated at 300–400 μm) than in larger pores at the implant exterior. The unit cell topology of the porous implant was also observed to guide the direction of bone ingrowth by conducting along the implant struts. These results suggest that in vivo experimentation is necessary alongside parametric optimization of functionally graded porous implants to predict short-term and long-term bone apposition.

Abstract 16545: Effect of Residual Risk of Inflammation and Lipoprotein(a) on Adverse Cardiovascular Outcomes in Optimally Treated Patients According to Glucose Tolerance Status

Introduction: Currently, risks of residual inflammation and residual lipoprotein(a) [Lp(a)] remains in patients with coronary artery disease (CAD) even after lipid-lowering therapy. Hypothesis: This study aims to investigate the association between dual residual risk of inflammation and Lp(a) and adverse cardiovascular events in a large, multicenter cohort with CAD, which has not been investigated. Methods: A total of 3,546 patients with CAD were consecutively enrolled. Based on the Lp(a) and hypersensitive C-reactive protein levels, patients were divided into those with no residual risk, residual Lp(a) risk (RLR), residual inflammatory risk (RIR), and residual cholesterol and inflammatory risk (RLIR). All patients were followed for the major adverse cardiovascular events (MACEs), including all cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Multivariable Cox proportional hazard model was conducted to determine hazard ratio (HR) of MACEs for RIR, RCR, and RCIR with different glucose tolerance status. Results: Over an average of 2.01 years follow-up, 326 MACEs were recorded. Multivariate Cox analysis showed that higher RIR were significantly related to an increased risk of MACEs, while elevated RLR were associated with a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RLR, RIR and glucose tolerance status together, High RLR+High RIR+Diabetes group had significantly higher risk of MACEs [hazard ratio (HR) 2.93, 95% confidence interval (CI) 1.71-5.02] compared with the reference group (Low RLR+Low RIR+Non-diabetes). Conclusions: The combination of RLR, RIR and glucose tolerance status potentiated the adverse effect on MACEs among statin-treated patients with CAD, suggesting that multiple residual risk factors assessment may be a better strategy to improve stratification in very-high risk population.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial

BackgroundIn the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence.Objectives and methodsAn open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS).ResultsPrior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points.ConclusionsOral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc’s potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.

Better post-operative outcomes at 1-year follow-up are associated with lower levels of pre-operative synovitis and higher levels of IL-6 and VEGFA in unicompartmental knee arthroplasty patients.

Osteoarthritis (OA) is associated with inflammation, and residual inflammation may influence outcomes following knee arthroplasty. This may be more relevant for patients undergoing unicompartmental knee arthroplasty (UKA) due to larger remaining areas of native tissue. This study aimed to: (1) characterise inflammatory profiles for medial UKA patients and (2) investigate whether inflammation markers are associated with post-operative outcomes. This prospective, observational study has national ethics approval. Bloods, synovial fluid, tibial plateaus and synovium were collected from medial UKA patients in between 1 January 2021 and 31 December 2021. Cytokine and chemokine concentrations in serum and synovial fluid (SF) were measured with multiplexed assays. Disease severity of cartilage and synovium was assessed using validated histological scores. Post-operative outcomes were measured with Oxford Knee Score (OKS), Forgotten Joint Score (FJS-12) and pain scores. The study included 35 patients. SF VEGFA was negatively correlated with pre-operative pain at rest (r -0.5, p = 0.007), and FJS-12 at six-week (r 0.44, p = 0.02), six-month (r 0.61, p < 0.01) and one-year follow-up (r 0.63, p = 0.03). Serum and SF IL-6 were positively correlated with OKS at early follow-up (serum 6weeks, r 0.39, p = 0.03; 6months, r 0.48, p < 0.01; SF 6weeks, r 0.35, p = 0.04). At six weeks, increased synovitis was negatively correlated with improvements in pain at rest (r -0.41, p = 0.03) and with mobilisation (r -0.37, p = 0.047). Lower levels of synovitis and higher levels of IL-6 and VEGFA were associated with better post-operative outcomes after UKA, which could be helpful for identifying UKA patients in clinical practice. Level IV case series.

Neonatal Zika virus infection causes transient perineuronal net degradation.

Perineuronal nets (PNNs) form a specialized extracellular matrix that predominantly surrounds parvalbumin (PV)-expressing GABAergic inhibitory interneurons and help regulate neuronal activity. Their formation early in the postnatal period is regulated by neuronal signaling and glial activation raising concerns that part of the long-term effects ascribed to perinatal viral infections could be mediated by altered PNN formation. Previously, we developed a model of neonatal Zika virus (ZIKV) infection where mice have lifelong neurological sequelae that includes motor disfunction and reduced anxiety coupled with a persistent low-grade expression in proinflammatory markers despite resolving the acute infection. Here, we demonstrate that ZIKV infection to P1 neonatal mice results in a reduction of PNN formation during the acute disease with significant reduction in Wisteria floribunda agglutinin (WFA) staining at the peak of infection [15 days post infection (dpi)] that persisted after the symptoms resolved (30 dpi). At 60 dpi, when there is residual inflammation in the CNS, the number of WFA+ cells and the level of WFA staining as well as levels of aggrecan and brevican in the brains of convalescent mice were not different from those in uninfected controls, however, there was increased frequency of PNNs with an immature phenotype. Over time the impact of the perinatal infection became less evident and there were no clear differences in PNN morphology between the groups at 1 year post infection. Of note, the reduction in PNNs during acute ZIKV infection was not associated with decreased mRNA levels of aggrecan or brevican, but increased levels of degraded aggrecan and brevican indicating increased PNN degradation. These changes were associated with increased expression of matrix metalloproteinase 12 (MMP12) and MMP19, but not MMP9, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) or ADAMTS5. Together our findings indicate that infection at the time of PNN development interferes with PNN formation, but the nets can reform once the infection and inflammation subside.

Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice.

We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders. Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression. We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival. Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.

Host-Reaction Following Silicone Tube Implantation For Lower Limb Lymphoedema Mimicking Implant Infection.

Silicone tube implantation in lymphoedema reduces symptoms by improving fluid drainage. Although there are descriptions of implant host reaction that can be misdiagnosed as graft infections these are scarce. A 34 year old female with lymphoedema of the lower limb, underwent silicone tube implantation. Ten months after surgery, the patient presented with fever and dermatolymphangioadenitis of the limb. Ultrasound suggested an abscess surrounding the tubes. Clinical improvement was achieved after a 6-day cycle of meropenem. She was discharged under oral cefuroxime and clindamycin for one week. After 1 month, CT-angiography was performed showing only residual inflammation surrounding the tubes, the patient was asymptomatic and limb diameter was normal. Sudden onset and improvement of the patient's condition after a short cycle of antibiotics without the need of tube removal supports a host-like reaction rather than an actual infection. Doctors should be aware of such complications avoiding unnecessary procedures.

Impact of obefazimod on viral persistence, inflammation, and immune activation in people with HIV on suppressive antiretroviral therapy.

Persistence of viral reservoirs has been observed in people with HIV (PWH), despite long-term ART, and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits HIV-1 replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed PWH. We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viraemia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed PWH who received daily doses of 50 mg of obefazimod for 12wks (n = 13), or 150 mg for 4wks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4wks. 50 or 150 mg doses of obefazimod were safe, although 150 mg dose showed inferior tolerability. 150 mg dose reduced HIV-1 DNA (p = 0.008, median fold-change = 0.6), and residual viraemia in all individuals with detectable viraemia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants, reduced the activation markers CD38, HLA-DR, and PD-1, and several inflammation biomarkers. The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.

Prevention and Treatment of Epitheliopathy as a Result of Acute Inflammatory Diseases of the Ocular Surface

Acute inflammatory diseases of the ocular surface occur in case of epitheliopathy. As a result, most patients complain of discomfort and persistence of residual inflammation after the infection has been stopped.The purpose: to assess the degree of damage to the ocular surface as a result of bacterial conjunctivitis and keratitis, as well as the regenerative effect of dexpanthenol 5 % eye gel on the healing and restoration of the functional activity of the ocular surface epithelium.Methods. A non-randomized case-control study was performed in patients with a bacterial infection of the conjunctiva and cornea. Under supervision there were 23 patients (46 eyes) diagnosed with bacterial conjunctivitis and 31 patients (31 eyes) with bacterial keratitis. According to the study design, patients were divided into two groups. After stopping the acute process, dexpanthenol 5 % eye gel was prescribed. To control the effectiveness, the tear film rupture time, the degree of damage to the mucin coating and surface epithelial cells were evaluated. Diagnostic tests with vital dyes (fluorescein (FA) and lyssamine green (LG)) were performed before the appointment of the gel, then seven and thirty days after the appointment of the drug.Results. After the relief of bacterial inflammation, 86.9 % patients with conjunctivitis and in all cases of keratitis had complaints (unpleasant sensations and redness of the eyes, blurred vision). There was a decrease in tear break-up time (TBUT) test, a significant accumulation of dye in the conjunctiva in both study groups and a partial accumulation of FA in the cornea, more intense in keratitis. After 7 days Corneregel use, there was an increase in TBUT compared to the baseline level, with a further increase in this indicator after a 1 month, a decrease in the manifestation of conjunctival epitheliopathy and the degree of corneal staining.Conclusions. The appointment of dexpanthenol 5 % eye gel after stopping a bacterial infection helps to relieve discomfort, accelerates the restoration of regeneration of the epithelial cells of the ocular surface, and increases the strength of the tear film.

High-risk Plaque Features Identify Residual Inflammation In Patients With Recent Acute Myocardial Infarction

High-risk Plaque Features Identify Residual Inflammation In Patients With Recent Acute Myocardial Infarction

Magnetic resonance imaging in naso-oropharyngeal carcinoma: role of texture analysis in the assessment of response to radiochemotherapy, a preliminary study

ObjectiveIdentifying MRI texture parameters able to distinguish inflammation, fibrosis, and residual cancer in patients with naso-oropharynx carcinoma after radiochemotherapy (RT-CHT).Material and methodsIn this single-centre, observational, retrospective study, texture analysis was performed on ADC maps and post-gadolinium T1 images of patients with histological diagnosis of naso-oropharyngeal carcinoma treated with RT-CHT. An initial cohort of 99 patients was selected; 57 of them were later excluded. The final cohort of 42 patients was divided into 3 groups (inflammation, fibrosis, and residual cancer) according to MRI, 18F-FDG-PET/CT performed 3–4 months after RT-CHT, and biopsy. Pre-RT-CHT lesions and the corresponding anatomic area post-RT-CHT were segmented with 3D slicer software from which 107 textural features were derived. T-Student and Wilcoxon signed-rank tests were performed, and features with p-value < 0.01 were considered statistically significant. Cut-off values—obtained by ROC curves—to discriminate post-RT-CHT non-tumoural changes from residual cancer were calculated for the parameters statistically associated to the diseased status at follow-up.ResultsTwo features—Energy and Grey Level Non-Uniformity—were statistically significant on T1 images in the comparison between ‘positive’ (residual cancer) and ‘negative’ patients (inflammation and fibrosis). Energy was also found to be statistically significant in both patients with fibrosis and residual cancer. Grey Level Non-Uniformity was significant in the differentiation between residual cancer and inflammation. Five features were statistically significant on ADC maps in the differentiation between ‘positive’ and ‘negative’ patients. The reduction in values of such features between pre- and post-RT-CHT was correlated with a good response to therapy.ConclusionsTexture analysis on post-gadolinium T1 images and ADC maps can differentiate residual cancer from fibrosis and inflammation in early follow-up of naso-oropharyngeal carcinoma treated with RT-CHT.

Subgingival instrumentation.

The S3-level clinical guidelines for the treatment of patients with periodontitis stages I-III published by the European Federation of Periodontology in 2020, suggest a pre-established stepwise approach for oral-healthcare professionals with precise therapeutic pathways. The second step of this approach consists of the subgingival instrumentation of periodontal pockets by non-surgical means to disrupt the microbial biofilm and remove soft and mineralized deposits This step aims to resolve periodontal inflammation by closure of periodontal pockets (probing pocket depth ≤ 4 mm, absence of bleeding on probing) employing different types of instruments and treatment protocols toward this end. Novel non-surgical treatment approaches that adopt micro instruments or subgingival application of biological agents have been recently tested. Subgingival instrumentation has been shown to effectively restore the subgingival microbiota to one associated with periodontal health and to modulate the inflammatory response. The outcomes of the subgingival instrumentation have to be evaluated in order to guide the therapist in providing additional but focused treatment in the remaining pockets OR at sites with residual inflammation. Of great importance is the impact that non-surgical periodontal treatment has on the patient's well-being, based on evidence that emerges from studies evaluating patient related outcomes and quality of life.

Changes in the molecular profiles of large-vessel vasculitis treated with biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors.

Giant cell arteritis and Takayasu arteritis are two types of primary large-vessel vasculitis (LVV). Although glucocorticoids (GC) are the standard treatment for LVV, the disease relapse rates are high. Recent clinical trials on biological disease-modifying anti-rheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors have demonstrated their efficacy in reducing LVV relapse rates and GC dosages. However, the control of residual inflammation and degenerative alterations in the vessel wall remains an outstanding requirement in the clinical management of LVV. The analysis of immune cell phenotypes in patients with LVV may predict their response to treatment with bDMARDs and JAK inhibitors and guide their optimal use. In this mini-review, we focused on molecular markers, including the immune cell proportions and gene expression, in patients with LVV and in mouse models of LVV treated with bDMARDs and JAK inhibitors.