Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs.

BACKGROUND AND PURPOSE: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.

Detection and comparison of neutrophil extracellular traps in tissue samples of peri-implantitis, periodontitis, and healthy patients: A pilot study.

OBJECTIVE: The aim of this study was to detect and compare the tissular expression of neutrophil extracellular traps (NETs) in peri-implant and periodontal samples of patients with peri-implantitis, periodontitis, and controls. MATERIALS AND METHODS: An observational study was performed on patients with peri-implantitis, periodontitis, and controls. Peri-implant and/or periodontal clinical examinations were performed on each participant. Tissue samples were collected during tooth/implant extraction for clinical reasons. Electron microscopy analysis, Picro-Sirius red staining, immunohistochemical (CD15), and immunofluorescence (citrullinated H3 and myeloperoxidase) techniques were performed to detect NET-related structures and the degree of connective tissue destruction, between the study groups. RESULTS: Sixty-four patients were included in the study: 28 peri-implantitis, 26 periodontitis, and 10 controls, with a total of 51 implants, 26 periodontal teeth, and 10 control teeth. Neutrophil release of nuclear content was observed in transmission electron microscopy. Immunohistochemical analysis showed a greater CD15 expression in both peri-implantitis and periodontitis compared to controls (p < 0.001), and peri-implantitis presented lower levels of connective tissue and collagen compared to both periodontitis (p = 0.044; p < 0.001) and controls (p < 0.001). Immunofluorescence showed greater citH3 expression in peri-implantitis than the one found in both periodontitis (p = 0.003) and controls (p = 0.048). CONCLUSIONS: A greater presence and involvement of neutrophils, as well as a greater connective tissue destruction were observed in cases of peri-implantitis. A higher expression of NET-related markers was found in mucosal samples of peri-implantitis compared to periodontitis and controls.

Correlation between Inflammasomes and Microbiota in Peri-Implantitis.

The activation of inflammasomes is thought to induce the inflammatory process around dental implants. No information is available on the correlation between microbiota and inflammasomes in clinical samples from patients suffering peri-implantitis. For this cross-sectional study, 30 biofilm samples were obtained from 19 patients undergoing surgical treatment for peri-implantitis because of the presence of bleeding on probing, probing depth higher than 6 mm, and radiographic bone loss higher than 3 mm. Then, soft tissue samples from around the implant were also collected. The relative abundance of bacteria and alpha-diversity indexes were calculated after analyzing the 16S rRNA gene using next-generation sequencing. The soft-tissue samples were processed for evaluation of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß. The relative abundance (mean (SD)) of specific species indicated that the most abundant species were Porphyromonas gingivalis (10.95 (14.17)%), Fusobacterium vincentii (10.93 (13.18)%), Porphyromonas endodontalis (5.89 (7.23)%), Prevotella oris (3.88 (4.94)%), Treponema denticola (2.91 (3.19)%), and Tannerella forsythia (2.84 (4.15)%). Several correlations were found between the species and the immunohistochemical detection of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß, both in the epithelium and the lamina propria. A network analysis found an important cluster of variables formed by NLRP3 in the lamina propria and AIM2, caspase-1, and IL-1ß in the lamina propria and the epithelium with Prevotella dentalis, Prevotella tannerae, Tannerella forsythia, or Selenomonas timonae. Thus, it could be concluded that inflammasomes NLRP3 and AIM2 and their downstream effectors caspase-1 and interleukin-1ß can be significantly associated with specific bacteria.

Periostin in the relation between periodontal disease and atherosclerotic coronary artery disease: A pilot randomized clinical study.

OBJECTIVE: The aim of this study was to analyze the effects of periodontal treatment on markers of atherosclerotic coronary artery disease and circulating levels of periostin. BACKGROUND: Periostin is necessary for periodontal stability, but it is highly present in atherosclerotic plaques. Treatment of periodontal disease, with low levels of local periostin, is thought to reduce systemic levels of periostin. Thus, this may contribute to cardiovascular health. METHODS: A pilot randomized controlled clinical trial was designed to include patients with severe periodontal disease and history of atherosclerotic coronary artery disease. Samples of gingival crevicular fluid (GCF) and serum were collected before and after periodontal treatment by periodontal surgery or non-surgical therapy. The levels of several markers of inflammation and cardiovascular damage were evaluated including CRP, IFN-γ, IL-1ß, IL-10, MIP-1α, periostin, and TNF-α in GCF and CRP, Fibrinogen, IFN-γ, IL-1ß, IL-6, IL-10, L-Selectin, MIP-1α, Periostin, TNF-α, and vWF in serum. RESULTS: A total of 22 patients with an average of 56 years old were recruited for participating in this study. Twenty of them were male. Most of them (82%) had suffered an acute myocardial event and underwent surgery for placing 1, 2, or 3 stents in the coronary arteries more than 6 months ago but less than 1 year. The treatment of periodontal disease resulted in an overall improvement of all periodontal parameters. Regarding the evaluation of GCF and serum, a significant increase of periostin in the GCF was observed after periodontal surgery. In contrast, although other markers in GCF and serum improved, no significant correlations were found. CONCLUSION: Treatment of periodontal disease through periodontal surgery induces a local and transient increase in the levels of periostin in the gingival crevicular fluid. The effects on systemic markers of inflammation and cardiovascular function have not been confirmed.

The Influence of History of Severe Periodontitis on Estimated Long-Term Marginal Bone Loss around Implants Restored with Fixed Segmented Full-Arch Rehabilitation.

The aim of this study was to analyze the long-term marginal bone level (MBL) of implants supporting fixed full-arch restoration in patients who had previously lost their dentition due to severe periodontitis. This retrospective study included 35 patients in whom 342 implants with internal tapered conical connections were placed. MBL was analyzed radiographically over time and a long-term estimation of MBL was calculated. A mixed linear model with abutment height, graft, diameter and location (maxilla/mandible) as factors and gender, age, implant length and prosthetic variables as covariates was used to evaluate the influence on MBL. MBL in these patients showed an estimator of predictions at 4108 days after loading of -0.307 mm, SE = 0.042. Only 0.15% of implants were radiographically affected with MBL of 3 mm or more. The mixed linear model results showed a main effect of the type of opposing dentition, gender, implant diameter, and abutment height. Particularly, an abutment height of 1 mm had associated larger MBL than the remaining heights. Thus, it can be concluded that dental implants restored with fixed segmented full-arch rehabilitation in patients with a history of severe periodontal disease do not suffer important marginal bone loss if some specific factors are considered, mainly the use of long transmucosal abutments (≥2 mm).

Inflammasomes NLRP3 and AIM2 in peri-implantitis: A cross-sectional study.

BACKGROUND: Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase-1 and IL-1ß. They have not been yet evaluated in samples from patients with active peri-implantitis. Thus, the aim of the present study is to analyze the expression of inflammasomes NLRP3 and AIM2 and subsequent caspase 1 and IL-1ß assessing the microenvironment of leukocyte subsets in samples from patients with active peri-implantitis. METHODS: Biopsies were collected from 33 implants in 21 patients being treated for peri-implantitis. Biopsies from gingival tissues from 15 patients with healthy periodontium were also collected for control. These tissues were evaluated through conventional histological stainings. Then, immunohistochemical detection was performed to analyze NLRP3, AIM2, caspase-1, and IL-1ß and markers of different leukocyte subsets. PCR for inflammasomes and related genes was also done. RESULTS: This manuscript reveals a high immunohistochemical and mRNA expression of NLRP3 and AIM2 inflammasomes, caspase-1, and IL-1ß in biopsies collected from human peri-implantitis. The expression of the tested markers was significantly correlated with the increase in inflammatory infiltrate, probing depth, presence of biofilm, and bleeding on probing. In these peri-implantitis lesions, the area of biopsy tissue occupied by inflammatory infiltrate was intense while the area occupied by collagen was significantly lower. In comparison with periodontal healthy tissues, the inflammatory infiltrate was statistically significantly higher in the peri-implantitis biopsies and was mainly composed of plasma cells, followed by T and B lymphocytes. CONCLUSION: In human peri-implantitis, chronic inflammation can be explained in part by the action of IL-1ß/caspase 1 induced through NLRP3 and AIM2 inflammasome activation.

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.

Physico-chemical and biological characterization of a new bovine bone mineral matrix available for human usage.

BACKGROUND: Anorganic bovine bone has been deeply studied for bone regeneration in the oral cavity. Different manufacturing processes can modify the final composition of the biomaterial and the responses that induce. AIM: To evaluate the physico-chemical characteristics of a bovine bone mineral matrix and the clinical, radiographical, histological, and mRNA results after using it for maxillary sinus floor augmentation in humans. MATERIALS AND METHODS: First, the physical-chemical characteristics of the biomaterial were evaluated by X-ray powder diffraction, X-ray fluorescence, and electron microscopy. A frequently used biomaterial with the same animal origin was used as comparator. Then, a clinical study was designed for evaluating clinical, radiographical, histological, and mRNA outcomes. Patients in need of two-stage maxillary sinus floor augmentation were included in the study. Six months after the grafting procedure, a bone biopsy was collected for evaluation. RESULTS: In terms of physico-chemical characteristics, no differences were found between both biomaterials. Clinically, 10 patients were included in the study. After 6 months, clinical and radiographical data showed adequate outcomes for allowing implant placement. Histological, immunohistochemical and mRNA analyses showed that the biomaterial in use provides biological support to induce responses similar to those of other commonly used biomaterials. CONCLUSION: Bovine bone mineral matrix (Creos™ Xenogain) used as a single material for maxillary sinus floor augmentation shows adequate biological, clinical, and radiological outcomes. In fact, the results from this study are similar to those reported in the literature for another bovine bone-derived biomaterial with whom it shares composition and micro- and nanoscale characteristics.

PARP inhibition promotes endothelial-like traits in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry.

Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM+ tumors. PARP inhibition and hypoxia modulated melanoma tube formation in vitro, inducing a more sparse and regular tubular architecture. Whole-transcriptome profiling revealed that olaparib treatment under hypoxic conditions modulated the expression of genes implicated in vasculogenesis during tube formation, enhancing the endothelial-like phenotype of VM+ uveal melanoma cells. PARP inhibition, especially during hypoxia, upregulated PDGFß, which is essential for pericyte recruitment. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM+ cells, modulate pericyte coverage, and reduce metastatic spread in VM+ melanoma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mineralocorticoid receptor blockade improved gut microbiota dysbiosis by reducing gut sympathetic tone in spontaneously hypertensive rats.

Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.

Density mapping of nerve endings in the skin of the palm and flexor retinaculum of the hand. Application to open carpal tunnel release.

In order to re-evaluate the safest area to incise skin and the flexor retinaculum (FR) when performing a carpal tunnel release (CTR), we carried out a mapping study of the nerve endings in the skin and FR on cadaver specimens, which, unlike previous studies for the first time, includes histomorphometry and image digital analysis. After dividing the skin and FR into 20 and 12 sections, respectively, we carried out a histomorphological analysis of nerve endings. The analysis was performed by two neutral observers on 4-µm histological sections stained with hematoxylin-eosin (H-E), and Klüver-Barrera with picrosirius red (KB + PR) methods. A semi-automatic image digital analysis was also used to estimate the percentage of area occupied per nerve. We observed a lower quantity of nerve endings in the skin of the palm of the hand in line with the ulnar aspect of the 4th finger. The ulnar aspect of the FR was the most densely innervated. However, there are no statistically significant differences between sections in the percentage of area occupied per nerve both in the skin and in the FR. We concluded that there is not a safe area to incise when performing carpal tunnel surgery, but taking into account the quantity of nerve endings present in skin and FR, we recommend an incision on the axis of the ulnar aspect of 4th finger when incising skin and on the middle third of the FR for CTR.

Limited marginal bone loss in implant-supported fixed full-arch rehabilitations after 5 years of follow-up.

PURPOSE: The aim of the present study was to evaluate the 5-year results in terms of marginal bone level (MBL) around implants supporting fixed full-arch metal-ceramic restorations in a series of cases of patients who had lost their teeth in that dental arch because of severe periodontal disease. MATERIAL AND METHODS: A retrospective cohort study was designed to evaluate the 5-year MBL results of OsseoSpeed™ Astra Tech TX implants with internal tapered conical connection. Age, gender, bone substratum, smoking habits, history of periodontitis, and prosthetic features were recorded. Mixed linear model was used to determine the influence of the different variables on MBL. RESULTS: In this series, a total of 160 implants placed in 19 patients were evaluated. No implant failure was reported during the 5 years of follow-up. Only 14 (8.75%) implants had more than 2 mm of MBL. Abutment height, F(3,142) = 6.917, p < .001, and implant diameter, F(1,141) = 15.059, p < .001, were determined to be statistically associated with MBL. No other effect was significant. Pairwise comparisons showed that MBL was larger for abutment height = 1 (MBL = -0.987, SE = 0.186) compared with the remaining heights [-0.335 (0.171), -0.169 (0.192) and -0.247 (0.267), 2, 4 and 6 mm, respectively]. MBL was larger for narrow (-0.510, SE = 0.169) than for wide implants (-0.364, SE = 0.190). CONCLUSION: The current study demonstrates that the vast majority of internal conical connection implants supporting fixed full-arch metal-ceramic restorations do not suffer from relevant MBL after 5 years in function. Particularly, those implants with transmucosal abutments longer than 2 mm show less than 0.5 mm from the implant shoulder to the marginal bone.

Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis.

Lysine specific demethylase 1 (LSD1; also known as KDM1A), is an epigenetic modulator that modifies the histone methylation status. KDM1A forms a part of protein complexes that regulate the expression of genes involved in the onset and progression of diseases such as cancer, central nervous system (CNS) disorders, viral infections, and others. Vafidemstat (ORY-2001) is a clinical stage inhibitor of KDM1A in development for the treatment of neurodegenerative and psychiatric diseases. However, the role of ORY-2001 targeting KDM1A in neuroinflammation remains to be explored. Here, we investigated the effect of ORY-2001 on immune-mediated and virus-induced encephalomyelitis, two experimental models of multiple sclerosis and neuronal damage. Oral administration of ORY-2001 ameliorated clinical signs, reduced lymphocyte egress and infiltration of immune cells into the spinal cord, and prevented demyelination. Interestingly, ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the inflammatory gene expression signature characteristic ofEAE in the CNS of mice more potently. In addition, ORY-2001 induced gene expression changes concordant with a potential neuroprotective function in the brain and spinal cord and reduced neuronal glutamate excitotoxicity-derived damage in explants. These results pointed to ORY-2001 as a promising CNS epigenetic drug able to target neuroinflammatory and neurodegenerative diseases and provided preclinical support for the subsequent design of early-stage clinical trials.

Early marginal bone loss around dental implants to define success in implant dentistry: A retrospective study.

PURPOSE: The aim of this study was to establish an objective criterion in terms of marginal bone level (MBL) to know the prognosis of an implant. MATERIALS AND METHODS: A group of 176 patients in whom 590 implants were placed were included in this retrospective study. Patients older than 18 years, presenting either Kennedy class I or II edentulous section, or totally edentulous at least in one of the dental arches were included in this study. Those with any type of disturbance able to alter bone metabolism or with nontreated periodontal disease were excluded. Data on radiographic MBL at loading, 6 and 18 months later, age, gender, smoking habits, history of periodontitis, bone substratum, implant, and prosthetic features were recorded. Nonparametric receiver operating curves (ROC) were constructed for the MBL at 18 months in order to establish a distinction among high bone loser (HBL) and low bone loser (LBL) implants. Differences as a function of main variables were also determined, particularly abutment height and periodontal disease. RESULTS: HBL implants lost at least 0.48 mm of MBL 6 months after loading; they reached at least 2 mm of MBL 18 months after loading. MBL rate followed a nonlinear trend, except in implants restored over long prosthetic abutments and in patients with history of severe periodontitis; in whom the rate of MBL over the time was nearly zero. CONCLUSION: Implants that lose more than 0.5 mm of marginal bone 6 months after loading are at great risk of not being radiographically successful anymore. Therefore, 0.5 mm of MBL is proposed as a distinctive and objective criterion of success in Implant Dentistry within a 6-month follow-up period. A prosthetic abutment height ≥2 mm resulted the most protective factor in the peri-implant bone maintenance.

Anorganic Bovine Bone Plus Recombinant Human Platelet-Derived Growth Factor-BB in Ridge Preservation: A Pilot Study.

PURPOSE: To determine clinical parameters, histologic features, and radiographic linear bone width changes of regenerated bone using different biomaterials for ridge preservation following tooth extraction. MATERIALS AND METHODS: For this pilot study, five patients were grafted with anorganic bovine bone and collagen plus recombinant human platelet-derived growth factor-BB (rhPDGF-BB), five patients were grafted with anorganic bovine bone and collagen alone, and five patients did not receive any biomaterial (control) after tooth extraction. Clinical, histologic, and radiographic evaluations were carried out 4 months postextraction. RESULTS: Differences in terms of buccolingual width were found when comparing the control group to the group grafted with anorganic bovine bone and collagen plus rhPDGF-BB (P = .012). No statistical differences were observed between the groups in terms of mineralized or nonmineralized tissue formation or in terms of the number of osteoblasts or osteocytes per mm2 after 4 months of healing. Interestingly, the number of vessels in the grafted area was found to be significantly different among the three groups (P = .005). The number of Musashi-1 positive cells was also different among groups, both in the mineralized and the nonmineralized areas of the grafted bone (P = .024 and .005, respectively). CONCLUSION: Anorganic bovine bone with bovine collagen is an efficient biomaterial to avoid postextraction resorption of the alveolar ridge. The addition of rhPDGF-BB appears to improve the biologic features of the newly formed bone and decrease bone resorption; further studies are needed for confirmation.

Maxillary sinus floor augmentation comparing bovine versus porcine bone xenografts mixed with autogenous bone graft. A split-mouth randomized controlled trial.

AIM: To compare the effectiveness of two xenografts for maxillary sinus floor augmentation in terms of clinical, radiographical, histologic, and molecular outcomes. MATERIALS AND METHODS: A split-mouth randomized clinical trial was conducted at the University of Granada. Ten consecutive patients in need of bilateral two-staged maxillary sinus floor augmentation were included. Each patient received both biomaterials (porcine bone mineral and anorganic bovine bone), which were randomly assigned for bilateral sinus augmentation. The maxillary autogenous bone scraped from the sinus access window was mixed with each xenograft at a 20:80 ratio. After a healing period of 6 months, bone biopsies were collected with a trephine during the implant placement in the regenerated area. Histologic, histomorphometrical, immunohistochemical, and molecular outcomes were analyzed. Clinical and radiographical data throughout the treatment phases were also evaluated. RESULTS: The resulting anatomic features were similar between both groups. After six months of graft consolidation, the graft resorption rates were similar between both biomaterials. The histologic, histomorphometrical, and immunohistochemical results showed no statistical differences between groups. CONCLUSION: Anorganic bovine bone and porcine bone mineral combined with maxillary autogenous cortical bone show similar biologic and radiologic features in terms of biomaterial resorption, osteoconduction, and osteogenesis when used for maxillary sinus floor augmentation.

SIDT1 plays a key role in type I IFN responses to nucleic acids in plasmacytoid dendritic cells and mediates the pathogenesis of an imiquimod-induced psoriasis model.

BACKGROUND: Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natural IFN-producing cells, the plasmacytoid dendritic cells (pDC). METHODS: The function of SIDT1 in pDC was determined by silencing its expression in human primary pDC and GEN2.2 cell line. SIDT1 role in vivo was assessed using the imiquimod-induced psoriasis model in the SIDT1-deficient mice (sidt1-/-). FINDINGS: Silencing of SIDT1 in GEN2.2 led to a blockade of the IFN-I response after stimulation of TLR7 and TLR9, without affecting the pro-inflammatory responses or upregulation of maturation markers. We found that SIDT1 migrates from the ER to the endosomal and lysosomal compartments together with TLR9 after CpG stimulation, participating in the access of the TLR9-CpG complex to lysosome-related vesicles, and therefore mediating the activation of TBK1 and the nuclear migration of IRF7, but not of NF-κB. sidt1-/- mice showed a significant decrease in severity parameters of the imiquimod-induced acute psoriasis-like model, associated with a decrease in the production of IFN-I and IFN-dependent chemokines. INTERPRETATION: Our findings indicate that SIDT1 is at the cross-road between the IFN-I and the proinflammatory pathways and constitutes a promising drug target for psoriasis and other diseases mediated by IFN-I responses. FUNDING: This work was supported by the Consejería de Salud y Familias de la Junta de Andalucía (PIER_S1149 and C2_S0050) and Instituto de Salud Carlos III (PI18/00082 and PI21/01151), partly supported by European FEDER funds, and prior funding to MEAR from the Alliance for Lupus Research and the Swedish Research Council.

Neuropeptide Cortistatin Regulates Dermal and Pulmonary Fibrosis in an Experimental Model of Systemic Sclerosis.

INTRODUCTION: Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy, and progressive fibrosis of the skin and internal organs. Because its aetiology is unknown, the identification of genes/factors involved in disease severity, differential clinical forms, and associated complications is critical for understanding its pathogenesis and designing novel treatments. Neuroendocrine mediators in the skin emerge as potential candidates. We investigated the role played by the neuropeptide cortistatin in a preclinical model of scleroderma. METHODS: Dermal fibrosis was induced by repetitive intradermal injections of bleomycin in wild-type and cortistatin-deficient mice. The histopathological signs and expression of fibrotic markers were evaluated in the skin and lungs. RESULTS: An inverse correlation between cortistatin levels and fibrogenic activation exists in the damaged skin and dermal fibroblasts. Bleomycin-challenged skin lesions of mice that are partially and totally deficient in cortistatin showed exacerbated histopathological signs of scleroderma, characterized by thicker and more fibrotic dermal layer, enlarged epidermis, and increased inflammatory infiltration in comparison to those of wild-type mice. Cortistatin deficiency enhanced dermal collagen deposits, connective tissue growth factor expression, loss of microvessels, and predisposition to suffer severe complications that co-occur with dermal exposition to bleomycin, including pulmonary fibrotic disease and increased mortality. Treatment with cortistatin mitigated these pathological processes. DISCUSSION/CONCLUSION: We identify cortistatin as an endogenous break of skin inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis of scleroderma and associated complications. Cortistatin-based therapies emerge as attractive candidates to treat severe forms of systemic sclerosis and to manage fibrosis-related side effects of bleomycin chemotherapy in oncologic patients.

Cortistatin regulates fibrosis and myofibroblast activation in experimental hepatotoxic- and cholestatic-induced liver injury.

BACKGROUND AND PURPOSE: Liver fibrosis induced by chronic hepatic injury remains a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis. EXPERIMENTAL APPROACH: We experimentally induced liver fibrosis in mice by chronic CCl4 exposure and bile duct ligation and evaluated the histopathological signs and fibrotic markers. KEY RESULTS: Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged by hepatotoxic and cholestatic injury. Compared with wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury. CONCLUSION AND IMPLICATIONS: We identify cortistatin as an endogenous molecular brake on liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that link with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various aetiologies.

The impact of tooth loss on cognitive function.

OBJECTIVE: To investigate if there is epidemiological evidence of an association between edentulism and cognitive decline beside that currently available from limited sample-sized case series and cross-sectional studies considering limited co-variables. MATERIALS AND METHODS: Data from two USA national health surveys [NHIS 2014-2017 and NHANES 2005-2018] were analyzed using multinomial logistic regression to study the impact of type of edentulism and number of remaining teeth on memory and concentration problems. Age, gender, socioeconomic status, education level, cardiovascular health index, body mass index, exercise, alcohol, smoking habits, and anxiety and depression were used as covariates. RESULTS: The combined population sample was 102,291 individuals. Age, socioeconomic status, educational level, anxiety and depression levels, and edentulism showed the highest odds ratios for cognitive decline. Number of teeth present in the mouth was found to be a predictor of cognitive status. This association showed a gradient effect, so that the lower the number of teeth, the greater the risk of exhibiting cognitive decline. CONCLUSIONS: Edentulism was found among the higher ORs for cognitive impairment. CLINICAL RELEVANCE: Maintenance of functional teeth through the promotion of oral health may contribute to the preservation of memory/concentration and other essential cognitive functions. Thus, increasing and efficiently coordinating efforts aimed at preventing of tooth loss in the adult population could substantially contribute to reduce the incidence of cognitive impairment.