Search

The aim of the present study is to analyze the effects of 5-aminoisoquinoline (5-AIQ), a poly(ADP-ribose) polymerase-1 (PARP1) inhibitor, over renal dysfunction and fibrosis during recovery phase of cisplatin (CisPt)-induced acute kidney injury (AKI) in rats. Male Wistar rats were distributed in three groups (n=8 each group): control, CisPt, and CisPt + 5-AIQ. Control and CisPt groups received a subcutaneous injection of either saline or 7 mg/kg CisPt, respectively. CisPt + 5-AIQ group received two intraperitoneal injections of 10 mg/kg 5-AIQ 2 h before and 24 h after CisPt treatment. Thirteen days after the treatment, rats were housed in metabolic cages and 24-h urine collection was made. At day 14, CisPt-treated rats showed increased diuresis, N-acetyl-β-D-glucosaminidase (NAG) excretion, glucosuria and sodium fractional excretion (NaFE), and decreased creatinine clearance (CrCl). 5-AIQ significantly increased CrCl and decreased NAG excretion, glucosuria, and NaFE. In plasma, CisPt increased sodium, urea, and creatinine concentrations, while 5-AIQ treatment decreased these variables to the levels of control group. 5-AIQ completely prevented the body weight loss evoked by CisPt treatment. CisPt also induced an increased renal expression of PAR polymer, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen-IV. These variables were decreased in CisPt + 5-AIQ group. Tubular lesions and renal fibrosis were also decreased by 5-AIQ treatment. We conclude that inhibition of PARP1 with 5-AIQ can attenuate long-term nephrotoxic effects associated with the CisPt treatment, preventing renal dysfunction and body weight decrease and ameliorating tubular lesions and collagen deposition. [ABSTRACT FROM AUTHOR]

Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes. [ABSTRACT FROM AUTHOR]

Background. Collagen-induced arthritis (CIA), a murine experimental disease model induced by immunization with type II collagen (CII), is used to evaluate novel therapeutic strategies for rheumatoid arthritis. Adult stem cell marker Musashi-1 (Msi1) plays an important role in regulating the maintenance and differentiation of stem/precursor cells. The objectives of this investigation were to perform a morphological study of the experimental CIA model, evaluate the effect of TNFα-blocker (etanercept) treatment, and determine the immunohistochemical expression of Msi1 protein. Methods. CIA was induced in 50 male DBA1/J mice for analyses of tissue and serum cytokine; clinical and morphological lesions in limbs; and immunohistochemical expression of Msi1. Results. Clinically, TNFα-blocker treatment attenuated CIA on day 32 after immunization (P<0.001). Msi1 protein expression was significantly higher in joints damaged by CIA than in those with no lesions (P<0.0001) and was related to the severity of the lesions (Spearman’s rho = 0.775, P=0.0001). Conclusions. Treatment with etanercept attenuates osteoarticular lesions in the murine CIA model. Osteoarticular expression of Msi1 protein is increased in joints with CIA-induced lesion and absent in nonlesioned joints, suggesting that this protein is expressed when the lesion is produced in order to favor tissue repair. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this pilot study was to investigate associations between IL-6 and COX-2 expression in gingival biopsies and both clinical diagnosis and genotypes in the IL-6 and COX-2 genes. Design: A case-control study included 41 gingival biopsies obtained from Caucasian patients grouped according to clinical diagnosis of gingival health (n = 10), gingivitis (n = 15) or chronic periodontitis (n = 16). Immunohistochemistry analyses were performed to determine COX-2 expression in lamina propria, IL-6 expression in lamina propria and gingival epithelium and level of inflammatory cell infiltrate. Individual DNA was extracted and genotyped by real-time PCR for IL6 SNPs rs 2069827 and rs 2069825 and for COX-2 rs 6681231. Results: The percentage of cellular COX-2 expression was associated with the extent of periodontal disease (Arbes index p = 0.026) and inflammatory infiltrate (p<0.0001). No association was observed between IL6 haplotypes and cells positive to IL-6 or COX-2 in gingival tissues. The COX-2 rs 6681231 was associated with cells positive to IL-6 in the connective tissue (p = 0.032). Conclusions: COX-2 expression in gingival tissues may be a marker of periodontal disease severity. COX-2 rs 6681231 may be associated with IL-6 local production in gingival tissues. [ABSTRACT FROM AUTHOR]

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). Materials and Methods: Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. Results: PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p= 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase-1 (PARP-1)-deficient mice are protected against septic shock, type I diabetes, stroke and inflammation. It is now accepted that inflammation and related events, such as activation of NF-?B, are key components in the initiation and progression of epithelial cancer and in particular in the neoplastic transformation of keratinocytes and skin carcinogenesis. Here, we report that PARP-1-deficient mice display a strikingly reduced susceptibility to skin carcinogenesis. In parp-1-/- mice, development of papilloma-like premalignant lesions induced with DMBA and TPA, is strongly delayed and the final number of tumor-bearing mice and total tumor number were significantly reduced. In addition, epidermis of parp-1-/- mice did not show increased proliferation rates after treatment with carcinogen. Deregulated NF-?B is a hallmark for tumorigenesis together with the concomitant release of early inflammatory mediators. In the absence of PARP-1, NF-?B activation and induction ?B-target genes did not take place during the promotion of tumor development. These results suggest that PARP-1 abolition impairs the promotion of skin carcinogenesis interfering with the activation of NF-?B and might have an important implication in targeting PARP-1 as a new antineoplastic therapeutic approach.Oncogene (2004) 23, 5275-5283. doi:10.1038/sj.onc.1207696 Published online 12 April 2004 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key results Conclusions and Implications 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.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.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.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. [ABSTRACT FROM AUTHOR]

In this study, we developed a quantitative method with digital image analysis to evaluate the degree of gingival overgrowth (GO). and compared GO in kidney transplant patients treated with cyclosporin A (CsA) (n=21) or CsA-nifedipine (n=8) and a group of healthy controls (n=30). The method was reproducible and reliable. Our findings showed significant differences in papillary and gingival surface between controls and transplant patients treated with GO inducers. Gingival overgrowth index also differed significantly between controls and each patient group (p<0.01, Kruskal-Wallis test). The administration of the calcium channel blocker nifedipine potentiated the adverse effect of CsA: comparison of the morphometric findings revealed significant differences between patients treated with CsA alone and CsA 1 nifedipine in papillary area, dental area, and GO index (p<0.01, Mann-Whitney U-test). We conclude that the method of image analysis we developed is useful in assessing the degree of GO. [ABSTRACT FROM AUTHOR]

Background: The age-related increase in blood pressure in spontaneously hypertensive rats (SHRs) is associated to cardiac hypertrophy, heart failure, and renal injury. Here, we investigated for the first time the urinary enzymatic activities of glutamil aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), and Klotho urinary levels, proteins that are strongly expressed in the kidney, as early biomarkers of renal injury in SHRs. Methods: Male SHR and Wistar Kyoto (WKY) rats were studied from 2 to 8 months old. Systolic blood pressure (SBP), the heart rate (HR), metabolic variables, and urinary markers were measured monthly. At the end of the study, a histopathological evaluation of the kidney was performed. Results: Kidneys of SHR did not develop signs of relevant histopathological changes, but showed increased glomerular area and cellularity. Plasma creatinine was decreased, and creatinine clearance was augmented in SHR at the end of the study. Urinary excretion of Klotho was higher in SHR at 5 and 8 months old, whereas plasma Klotho levels were similar to WKY. GluAp, AlaAp, and DPP4 urinary activities were increased in SHR throughout the time-course study. A positive correlation between glomerular area and cellularity with creatinine clearance was observed. Urinary GluAp, AlaAp, DPP4, and Klotho showed positive correlations with SBP. Conclusions: GluAp, AlaAp, DPP4, and Klotho in the urine are useful tools for the evaluation of renal damage at early stages, before the whole histopathological and biochemical manifestations of renal disease are established. Moreover, these observations may represent a novel and noninvasive diagnostic approach to assess the evolution of kidney function in hypertension and other chronic diseases. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the expression of Musashi-1 (MSI1) in maxillary native bone and grafted bone after maxillary sinus floor elevation. To do so, fifty-seven bone biopsies from 45 participants were studied. Eighteen samples were collected from native bone while 39 were obtained 6 months after maxillary sinus grafting procedures. Musashi-1 was analyzed by immunohistochemistry and RT-PCR. MSI1 was detected in osteoblasts and osteocytes in 97.4% (38/39) of grafted areas. In native bone, MSI1 was detected in only 66.6% (12/18) of the biopsies, mainly in osteocytes. Detection of MSI1 was significantly higher in osteoprogenitor mesenchymal cells of grafted biopsies (p < 0.001) but minor in smooth muscle and endothelial cells; no expression was detected in adipocytes. The mesenchymal cells of the non-mineralized tissue of native bone showed very low nuclear expression of MSI1, in comparison to fusiform cells in grafted areas (0.28(0.13) vs. 2.10(0.14), respectively; p < 0.001). Additionally, the detection of MSI1 mRNA was significantly higher in biopsies from grafted areas than those from native bone (1.00(0.51) vs. 60.34(35.2), respectively; p = 0.029). Thus, our results regardig the significantly higher detection of Musashi-1 in grafted sites than in native bone reflects its importance in the remodeling/repair events that occur after maxillary sinus floor elevation in humans. [ABSTRACT FROM AUTHOR]

Background: We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). Methods: We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment. Results: The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. Conclusions: Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

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-1β. 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-1β, 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-1β 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-1β can be significantly associated with specific bacteria. [ABSTRACT FROM AUTHOR]

Background: Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase‐1 and IL‐1β. 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‐1β 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‐1β 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‐1β 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‐1β/caspase 1 induced through NLRP3 and AIM2 inflammasome activation. [ABSTRACT FROM AUTHOR]

Background: Poly (lactic‐co‐glycolic acid) (PLGA) is widely used for the development of delivery systems for drugs and therapeutic biomolecules in tissue engineering applications. Particles of biphasic calcium phosphate can be covered by PLGA to change their manipulating characteristics. Purpose: Aim of this study was to investigate the radiological and histomorphometric results of the use of PLGA‐coated biphasic calcium phosphate granules in sinus floor elevation and to analyze the underlying molecular processes by immunohistochemical staining. Materials and Methods: A randomized clinical study was designed to include patients in need of sinus floor elevation. Patients were assigned to receive either PLGA‐coated biphasic calcium phosphate particles (group I) or the equivalent but noncoated particles (group II). Cone beam computed tomography (CBCT) scans were performed before and 6 months after the procedure to assess the bone height gain. At the time of implant placement, bone core biopsies were obtained at the site of implant placement. Histological sections were subjected to histomorphometric and immunohistochemical evaluation of differentiation markers (Musashi‐1 [MSI1]). Results: No statistically significant differences were observed between groups for the radiologic parameters. No differences were observed histologically or histomorphometrically. However, PLGA‐coated particles (group I) were more colonized by MSI1‐positive osteoblast precursors (P = 0.0001, chi‐squared test) and were penetrated by more CD34‐positive vascular structures (P = 0.001, chi‐squared test) than noncoated particles (group II). Conclusions: PLGA‐coated particles are associated with more MSI11‐positive cells and more extensive microvascularization than noncoated particles. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising therapy for autoimmune diseases, including multiple sclerosis (MS). Administration of MSCs to MS patients has proven safe with signs of immunomodulation but their therapeutic efficacy remains low. The aim of the current study has been to further characterize the immunomodulatory mechanisms of adipose tissue-derived MSCs (ASCs) in vitro and in vivo using the EAE model of chronic brain inflammation in mice. We found that murine ASCs (mASCs) suppress T cell proliferation in vitro via inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX-) 1/2 activities. mASCs also prevented the lipopolysaccharide- (LPS-) induced maturation of dendritic cells (DCs) in vitro. The addition of the COX-1/2 inhibitor indomethacin, but not the iNOS inhibitor L-NAME, reversed the block in DC maturation implicating prostaglandin (PG) E2 in this process. In vivo, early administration of murine and human ASCs (hASCs) ameliorated myelin oligodendrocyte protein- (MOG35-55-) induced EAE in C57Bl/6 mice. Mechanistic studies showed that mASCs suppressed the function of autoantigen-specific T cells and also decreased the frequency of activated (CD11c+CD40high and CD11c+TNF-α+) DCs in draining lymph nodes (DLNs). In summary, these data suggest that mASCs reduce EAE severity, in part, through the impairment of DC and T cell function. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to determine whether clinical periodontal parameters are associated with plasma anti- and/or pro-inflammatory cytokines in pregnant woman with preterm birth (PB) or low birth weight (LBW) neonates. Materials and methods: An observational case-control study was performed in 131 puerperal women: mothers of PB/LBW neonates (cases, n = 67) and mothers of full-term normal-weight neonates (controls, n = 64). Sociodemographic and periodontal data was gathered from all participants, and interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17, IL-23, and tumor necrosis factor alpha (TNF-α) were determined in plasma. Results: In multiple linear regression models, clinical attachment loss was associated with TNF-α (0.28 ± 0.14; 95 % confidence interval (CI) [0.006, 0.553]) and IL-1β (0.43 ± 0.21; 95 %CI [0.018, 0.842]), independent of group membership. IL-1β (−1.67 ± 0.27, 95 %CI [−2.199, −1.141]), IL-6 (−0.86 ± 0.27; 95 %CI [−1.389, −0.331]), and IL-8 (−3.84 ± 0.50, 95 %CI [−4.820, −2.860]) were lower, and IL-10 (0.86 ± 0.26; 95 %CI [0.350, 1.370]) was higher in cases versus controls after adjusting for potential confounders. Conclusions: Clinical attachment loss was associated with plasma TNF-α and IL-1β levels. No plasma cytokine profiles suggestive of systemic inflammatory response were observed in the pregnant women with PB/LBW neonates. Clinical relevance: Clinical attachment loss, as the main periodontal measure, is associated with TNF-α and IL-1β plasma levels in pregnant women. No relationship was found between PB/LBW and the markers of systemic inflammatory response assessed in this study. [ABSTRACT FROM AUTHOR]

Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to evaluate the vertical and horizontal graft bone resorption ( GR) in grafted maxillary sinuses and the marginal bone loss ( MBL) around implants placed in the sinuses with different prosthetic connections and to determine the effect of other clinical factors on these tissue responses at 6 and 18 months postloading. Material and Method A total of 254 implants were placed in 150 grafted maxillary sinuses of 101 patients (51.5% female) with mean age of 52.2 years (range, 32-82 years). GR and MBL measurements were made in implants placed with two different prosthetic connections (internal and external) at 6 and 18 months postloading. The complex samples general linear model was used to analyze the influence of patient age, gender, smoking habit, history of periodontal disease, implantation timing (simultaneous vs deferred), and prosthetic abutment length on radiographic GR and MBL values. Results At 18 months postloading, the MBL ranged from 0 mm to 5.89 mm; less than 1 mm was lost around 49.0% (mesial) and 44.3% (distal) of the implants, while no bone was lost around 32.9% (mesial) and 26.7% (distal). The GR was significantly affected by smoking, remnant alveolar bone height, graft length, graft height, gender, and age, and it significantly decreased over time. The MBL was influenced by the type of connection, implantation timing, and prosthetic abutment length. The MBL was greater with longer postloading interval and higher patient age and in smokers. Conclusion Resorption of grafts that combine autogenous cortical bone with anorganic bovine bone is dependent on the anatomic features of the sinus and is not affected by the time elapsed after the first 6 months. The MBL in implants placed in these grafted areas is time dependent and mainly related to potentially modifiable clinical decisions and patient habits. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6-30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species. We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane. The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities. Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis. Moreover, treatment with VIP51(6-30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens. [ABSTRACT FROM AUTHOR]

Objective Rheumatoid arthritis (RA) is an autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Cells isolated from human amniotic membrane (HAMCs) were recently found to display immunosuppressive properties. The aim of this study was to characterize the effect of HAMCs on antigen-specific T cell responses in RA patients and to evaluate their therapeutic potential in a preclinical experimental model of RA. Methods We investigated the effects of HAMCs on collagen-reactive T cell proliferation and cytokine production, on the production of mediators of inflammation by synoviocytes, and on the generation of Treg cells in peripheral blood mononuclear cells and synovial membrane cells isolated from RA patients. Mice with collagen-induced arthritis (CIA) were treated with HAMCs after disease onset, and clinical scores and joint levels of mediators of inflammation were evaluated. We determined Th1/Th17-mediated autoreactive responses in the mice by measuring the proliferation and the cytokine profile of lymph node cells restimulated with collagen. Results Treatment with HAMCs suppressed synovial inflammatory responses and antigen-specific Th1/Th17 activation in cells isolated from RA patients. Moreover, HAMCs stimulated the generation of human CD4+CD25+FoxP3+ Treg cells with a capacity to suppress collagen-specific T cell responses. Systemic infusion of HAMCs significantly reduced the incidence and severity of CIA by down-regulating the 2 deleterious components of disease: Th1-driven autoimmunity and inflammation. In mice with CIA, HAMC treatment decreased the production of various inflammatory cytokines and chemokines in the joints, impaired antigen-specific Th1/Th17 cell expansion in the lymph nodes, and generated peripheral antigen-specific Treg cells. HAMCs also protected the mice from experimental sepsis, inflammatory bowel disease, and autoimmune encephalomyelitis. Conclusion HAMCs have emerged as attractive candidates for a cell-based therapy for RA. [ABSTRACT FROM AUTHOR]

The authors are correcting this article because they accidentally included some wrong data in the analysis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and a healthcare burden in critically ill patient. There is an urgent need to identify factors causing susceptibility and for the design of new therapeutic agents. Here, we evaluate the effectiveness of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo.Experimental Approach: ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines, and fibrotic markers were evaluated.Key Results: Partially deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis, after high exposure to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin and ghrelin receptors.Conclusion and Implications: We identified cortistatin as an endogenous inhibitor of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies could emerge as attractive candidates to treat severe ALI/ARDS, including SARS-CoV-2-associated ARDS. [ABSTRACT FROM AUTHOR]

PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hypertension is an important cardiovascular risk factor that is prevalent in the systemic lupus erythematosus patient population. Here, we have investigated whether intestinal microbiota is involved in hypertension in a genetic mouse model of systemic lupus erythematosus. Experimental Approach Twenty‐six‐week‐old female NZW/LacJ (control) and NZBWF1 (F1 hybrid of New Zealand Black and New Zealand White strains; systemic lupus erythematosus) mice were treated for 6 weeks with a broad‐spectrum antibiotic mixture or with vancomycin. Faecal microbiota transplantation was performed from donor systemic lupus erythematosus group to recipient to germ‐depleted or germ‐free mice. Key Results: Antibiotic treatment inhibited the development of hypertension and renal injury, improved endothelial dysfunction and vascular oxidative stress, and decreased aortic Th17 infiltration in NZBWF1 mice. High BP and vascular complications found in systemic lupus erythematosus mice, but not autoimmunity, kidney inflammation and endotoxemia, were reproduced by the transfer of gut microbiota from systemic lupus erythematosus donors to germ‐free or germ‐depleted mice. Increased proportions of Bacteroides were linked with high BP in these mice. The reduced endothelium‐dependent vasodilator responses to acetylcholine and the high BP induced by microbiota from hypertensive systemic lupus erythematosus mice were inhibited after IL‐17 neutralization. Conclusion and Implications: Changes in T‐cell populations, endothelial function, vascular inflammation and hypertension driven by a genetic systemic lupus erythematosus background can be modified by antibiotic‐induced changes in gut microbiota. The vascular changes induced by hypertensive systemic lupus erythematosus microbiota were mediated by Th17 infiltration in the vasculature. [ABSTRACT FROM AUTHOR]

Background Flexor retinaculum reconstruction techniques or simply Flexor Retinaculum Z -lengthening have been proposed to preserve Flexor Retinaculum continuity after carpal tunnel release. Their effectiveness is based solely on symptom relief. There has been no analysis of the effects on intra-carpal tunnel pressure of Flexor Retinaculum-lengthening techniques. Objective was to compare intra-carpal tunnel pressure outcomes between complete division and Z -lengthening of the Retinaculum in a cadaveric model of carpal tunnel release. Methods Experimental study of carpal tunnel pressure after surgical Flexor Retinaculum modification in 10 fresh-frozen forearm and hand cadaveric specimens. The Kyphon™ Balloon Kyphoplasty system was used to measure the pressure before and after infusing 1, 2, 3, 4 and 5 ml of saline solution when untreated (Flexor Retinaculum continuity stage I), when Z -lengthened (Flexor Retinaculum continuity stage II), and after complete Flexor Retinaculum division (Flexor Retinaculum continuity stage III). Finding Intra-carpal tunnel pressure increased with larger volume of infused saline solution, although mean pressures were lower after Z lengthening or complete division of the Retinaculum than at baseline. Analysis of linear regression coefficients indicated significant differences as a function of FR continuity stage (F(2,18) = 18.38, p < 0.001), while the Bonferroni test revealed significant differences in slopes between stages I and III (p = 0.003), between stages I and II (p < 0.02), but not between stages II and III (p > 0.05). Interpretation The effectiveness of carpal tunnel release and the reduction in intra-carpal tunnel pressures obtained by Z -lengthening of the FR were similar to those observed after its complete division, while preserving FR continuity. • Carpal Tunnel Syndrome. • Flexor Retinaculum reconstruction technique. • Flexor Retinaculum lengthening techniques. • Carpal tunnel pressure. [ABSTRACT FROM AUTHOR]

Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis. [ABSTRACT FROM AUTHOR]

Objectives: To analyze a modified biphasic phycogenic biomaterial in comparison with anorganic bovine bone in maxillary sinus floor elevation in humans. Material and methods: Eight male patients in need of bilateral two‐stage sinus floor elevation were consecutively recruited for this randomized split‐mouth study. A combination of autogenous cortical bone (ACB, 20%) and anorganic bovine bone (ABB, 80%) (ACB + ABB group) or ACB (20%) and modified biphasic phycogenic material (BP, 80%) (ACB + BP group) were randomly assigned to graft each sinus. Patients were followed up for 6 months post‐surgery when bone samples were collected for analysis. Results: Radiographically, bone height gain was statistically higher in the ACB + ABB versus the ACB + BP group. While the analysis of the biological compartments showed differences in non‐mineralized tissue (39.15 ± 20.97% vs. 65.87 ± 28.59%, ACB + ABB vs. ACB + BP respectively; p =.018) and remnant biomaterial particles (22.62 ± 17.01% vs. 7.96 ± 8.57%, respectively; p =.028), the percentage of mineralized tissue (38.23 ± 17.55% vs. 24.14 ± 24.66%, respectively; p =.398) showed no statistically significant difference. In contrast, ACB + ABB biopsies showed higher Musashi‐1‐positive cells per mm2 compared to ACB + BP biopsies (811.49 ± 875.30 vs. 236.90 ± 280.81; p <.018), where the fusiform cells corresponded mainly with fibroblasts, as demonstrated by ultrastructural analysis. Conclusion: Both combinations of materials exhibited bone formation after 6 months of healing in the maxillary sinus cavity. However, the combination with biphasic phycogenic biomaterial induced a higher radiographical vertical resorption and graft collapse in comparison with the combination with anorganic bovine bone, possibly due to a higher remodeling of the graft. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine whether the immune-modulatory bacteria Lactobacillus fermentum CECT5716 (LC40) ameliorates disease activity and cardiovascular complications in a female mouse model of lupus. Eighteen-week-old NZBWF1 [systemic lupus erythematosus (SLE)] and NZW/LacJ (control) mice were treated with vehicle or LC40 (5 × 108 colony-forming units/d) for 15 wk. LC40 treatment reduced lupus disease activity, blood pressure, cardiac and renal hypertrophy, and splenomegaly in SLE mice. LC40 reduced the elevated T, B, regulatory T cells (Treg), and T helper (Th)-1 cells in mesenteric lymph nodes of lupus mice. LC40 lowered the higher plasma concentration of proinflammatory cytokines observed in lupus mice. Aortas from SLE mice showed reduced endothelium-dependent vasodilator responses to acetylcholine. Endothelial dysfunction found in SLE is related to an increase of both NADPH oxidase-driven superoxide production and eNOS phosphorylation at the inhibitory Thr495. These activities returned to normal values after a treatment with LC40. Probiotic administration to SLE mice reduced plasma LPS levels, which might be related to an improvement of the gut barrier integrity. LC40 treatment increases the Bifidobacterium count in gut microbiota of SLE mice. In conclusion, our findings identify the gut microbiota manipulation with LC40 as an alternative approach to the prevention of SLE and its associated vascular damage. [ABSTRACT FROM AUTHOR]

Kidney fibrosis is one of the main pathological findings of progressive chronic kidney disease (CKD) although the pathogenesis of renal scar formation remains incompletely explained. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix (ECM) and intracellular signaling pathways, is involved in several pathophysiological processes during renal damage. However, ILK contribution in the CKD progress remains to be fully elucidated. In the present work, we studied 1) the renal functional and structural consequences of CKD genesis and progression when ILK is depleted and 2) the potential of ILK depletion as a therapeutic approach to delay CKD progression. We induced an experimental CKD model, based on an adenine-supplemented diet on adult wild-type (WT) and ILK-depleted mice, with a tubulointerstitial damage profile resembling that is observed in human CKD. The adenine diet induced in WT mice a progressive increase in plasma creatinine and urea concentrations. In the renal cortex it was also observed tubular damage, interstitial fibrosis and progressive increased ECM components, pro-inflammatory and chemo-attractant cytokines, EMT markers and TGF-β1 expressions. These observations were highly correlated to a simultaneous increase of ILK expression and activity. In adenine-fed transgenic ILK-depleted mice, all these changes were prevented. Additionally, we evaluated the potential role of ILK depletion to be applied after the disease induction, as an effective approach to interventions in human CKD subjects. In this scenario, two weeks after the establishment of adenine-induced CKD, ILK was abrogated in WT mice and stabilized renal damage, avoiding CKD progression. We propose ILK to be a potential target to delay renal disease progression. • The adenine-induced mouse model of CKD shows increased ILK expression and activity. • ILK depletion prevents the structural and functional progression of induced CKD. • ILK depletion provides mechanisms to protect against fibrosis, EMT and Inflammation. • After CKD has started ILK abrogation stabilized and avoided progression to end-stage. • This emphasizes the potential application of ILK blockade in clinical practice. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E-deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]

It is estimated that six million perinatal deaths occur every year worldwide, with premature birth being the main cause. Scientific evidence has shown that there is an association between periodontal health during pregnancy and adverse outcomes of labor, although interventional studies based on the treatment of periodontitis have failed to document an impact on reducing the incidence of preterm birth (PB) or low birth weight (LBW). Two pathogenic mechanisms have been proposed to explain this association. The direct pathway is based on the presence of gram-negative anaerobic bacteremia originating in the gingival biofilm, whereas the indirect pathway involves the production of pro-inflammatory markers which enter the bloodstream from the gingival submucosa. The result is the same: the development of an immune inflammatory response and/or the local suppression of growth factors in the fetal–placental unit, which in turn triggers labor. In the present review, we describe current concepts pertinent to PB and LBW, chronic and aggressive periodontitis, and the most frequent aspects of periodontal pathology during pregnancy. We evaluate the scientific evidence available to date, and offer a detailed description of the two pathways proposed to explain the association of maternal periodontitis with preterm and LBW delivery. [ABSTRACT FROM PUBLISHER]

Objective: To compare the clinical and histologic outcomes of two different grafting materials (allograft and xenograft) when combined with autogenous bone and covered with a collagen membrane for sinus augmentation. Material and Methods: A parallel case series of fourteen patients in need of a unilateral sinus augmentation was evaluated in this study. Seven patients received a graft composed by autologous cortical bone (ACB) and anorganic bovine bone in a ratio of 1:1; the other seven patients received ACB mixed with an allograft in the same ratio. Bone biopsies were obtained 6 months after sinus augmentation at the time of implant placement. Comparative histomorphometrical, histopathological, and immunohistochemical analyses were conducted and statistically analyzed. Results: After 12 months of functional loading, all implants in both groups were clinical and radiographically successful. Histomorphometrically, although the initial bone formation was not significantly different between groups (new mineralized tissue: 41.03(12.87)% vs. 34.50(13.18)%, p = .620; allograft vs. xenograft groups), the graft resorbed faster in the allograft group (remnant graft particles: 9.83[7.77]% vs. 21.71[17.88]%; p = .026; allograft vs. xenograft groups). Non‐mineralized tissue did not statistically differ either (49.00[14.32]% vs. 43.79[19.90]%; p = .710; allograft vs. xenograft groups). The histologic analyses revealed higher cellular content, four times more osteoid lines, and higher vascularization in the xenograft group. Musashi‐1 (mesenchymal stromal cell marker) was also more intensively expressed in the xenograft group (p = .019). Conclusions: Both composite grafts generate adequate substratum to receive dental implants after healing. Compared with the xenograft composite, allograft composite shows faster turnover and a quicker decrease in biological action after 6 months. [ABSTRACT FROM AUTHOR]

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. [Display omitted] ● Spironolactone reduces systolic blood pressure and improves gut dysbiosis in SHR. ● The improvement of gut dysbiosis was associated with an enhanced colonic integrity. ● Spironolactone inhibited sympathetic drive in the gut. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to investigate if the content of glutamyl aminopeptidase (GluAp) in microvesicular and exosomal fractions of urine is related with renal dysfunction in cisplatin-treated rats. Methods: Urine samples were collected 24 hours after injection of cisplatin (7 mg/kg, n = 10) or saline serum (n = 10), and they were subjected to differential centrifugation at 1.000, 17.000 and 200.000 g to obtain microvesicular and exosomal fractions. GluAp was measured with a commercial ELISA kit in both fractions. Serum creatinine (SCr) and body weight were measured 15 days after treatment. We analyzed if early excretion of GluAp in microsomal and exosomal fractions was correlated with final SCr and body weight increase. In a second experiment, enzymatic activities of GluAp and alanyl aminopeptidase (AlaAp) in urine, microvesicular and exosomal fractions were measured three days after injection. We analyzed the correlation of both markers with SCr determined at this point. Finally, we studied the expression of GluAp and extracellular vesicles markers Alix and tumor susceptibility gene (TSG101) in both fractions by immunoblotting. Results: GluAp excretion was increased in all fractions of urine after cisplatin treatment, even if data were normalized per mg of creatinine, per body weight or per total protein content of each fraction. We found significant predictive correlations with SCr concentration, and inverse correlations with body weight increase determined 15 days later. Three days after injection, aminopeptidasic activities were markedly increased in all fractions of urine in cisplatin-treated rats. The highest correlation coefficient with SCr was found for GluAp in microvesicular fraction. Increase of GluAp in microvesicular and exosomal fractions from cisplatin-treated rats was confirmed by immunoblotting. Alix and TSG101 showed different patterns of expression in each fraction. Conclusions: Determination of GluAp content or its enzymatic activity in microvesicular and exosomal fractions of urine is an early and predictive biomarker of renal dysfunction in cisplatin-induced nephrotoxicity. Measurement of GluAp in these fractions can serve to detect proximal tubular damage independently of glomerular filtration status. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myocarditis is an inflammatory and autoimmune cardiovascular disease that causes dilated myocardiopathy and is responsible for high morbidity and mortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of the immune and vascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM).Experimental Approach: We induced EAM by immunization with a fragment of cardiac myosin in susceptible Balb/c mice. Cortistatin was administered i.p. starting 7, 11 or 15 days after EAM induction. At day 21, we evaluated heart hypertrophy, myocardial injury, cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation.Key Results: Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation between cardiac and systemic cortistatin levels and EAM severity.Conclusions and Implications: Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background Bone morphogenetic proteins ( BMPs) are members of the transforming growth factor- β ( TGFβ) protein superfamily and are known to be involved in bone and cartilage formation. Within this family, BMP-4 is one of the most studied members. It has been shown to induce osteogenic differentiation of osteoblasts and osteoprogenitor cells in vitro, but the intimate processes in which this protein promotes and regulates osseous repair still remains unclear. Purpose To assess whether the native cellular immunohistochemical expression of BMP-4 correlates with the maturation of bone samples obtained at 6 months after maxillary sinus augmentation. Materials and Methods Histopathological and histomorphometrical analyses were performed in all the samples, which were obtained from a total of 58 patients. Immunohistochemical expression of BMP-4 was analyzed in 30 core biopsies obtained from maxillary sinuses grafted with a combination of anorganic bovine bone and autogenous cortical bone [1:1] ( AB-group), and 18 biopsies from maxillary sinuses grafted solely with a cortico-cancellous particulate allograft ( M-group), all of them after a 6-month healing period. Also, 10 biopsies of native pristine bone were obtained and used as control group ( C-group). Results Mild to moderate immunohistochemical expression of native granular BMP-4 was present in 56.8% (31.0% AB-group, 22.4% M-group, and 3.4% C-group) ( p = 0.000, chi-square) of the specimens analyzed. BMP-4 expression was primarily located in the cytoplasm of osteoblasts, osteoclasts, and epithelial cells of the schneiderian membrane. Whereas significant differences were observed in the proportion of mineralized tissue and cellularity between sinuses grafted with anorganic bovine bone, allograft, or nongrafted sinuses, there were no statistically significant differences in the cellular expression of BMP-4 among groups. Conclusion Our findings suggest that the native expression of BMP-4 appears to be associated with normal bone homeostasis and reparation in grafted and nongrafted maxillary sites. [ABSTRACT FROM AUTHOR]

Purpose The purpose was to radiographically analyze and compare the marginal bone loss ( MBL) between implants with different mismatching distance and to study the influence of the prosthetic abutment height on the MBL in association with the related mismatching distances. Material and methods This retrospective study included 108 patients in whom 228 implants were placed, 180 with diameter of 4.5 mm and 48 with diameter of 5 mm. All patients received OsseoSpeed™ implants with internal tapered conical connection (Denstply Implants). Different mismatching distances were obtained, given that all implants were loaded with the same uni-abutment type (Lilac; Denstply Implants). Data were gathered on age, gender, bone substratum, smoking habits, previous history of periodontitis, and prosthetic features. MBL was analyzed radiographically at 6 and 18 months post-loading. Results Mixed linear analysis of mesial and distal MBL values yielded significant effects of abutment, implant diameter, follow-up period, bone substratum, smoking, and abutment × time interaction. MBL was greater at 18 vs. 6 months, for short vs. long abutments, for grafted vs. pristine bone, for a heavier smoking habit, and for implants with a diameter of 5.0 vs. 4.5 mm. Conclusion Greater mismatching does not minimize the MBL; abutment height, smoking habit, and bone substratum may play a role in the MBL over the short- and medium term. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to analyze marginal bone loss ( MBL) rates around implants to establish the difference between physiological bone loss and bone loss due to peri-implantitis. Materials and methods Five hundred and eight implants were placed in the posterior maxilla in 208 patients. Data were gathered on age, gender, bone substratum (grafted or pristine), prosthetic connection, smoking and alcohol habits, and previous periodontitis. MBL was radiographically analyzed in three time frames (5 months post-surgery and at 6 and 18 months post-loading). Nonparametric receiver operating curve ( ROC) analysis and mixed linear model analysis were used to determine whether implants could be classified as high or low bone loser type ( BLT) and to establish the influence of this factor on MBL rates. Results Marginal bone loss rates were significantly affected by BLT, connection type, bone substratum, and smoking. Bone loss rates at 18 months were associated with initial bone loss rates: 96% of implants with an MBL of >2 mm at 18 months had lost 0.44 mm or more at 6 months post-loading. Conclusion Implants with increased MBL rates at early stages (healing and immediate post-loading periods) are likely to reach MBL values that compromise their final outcome. Initial (healing, immediate post-loading) MBL rates around an implant of more than 0.44 mm/year are an indication of peri-implant bone loss progression. [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationship of tobacco consumption with alveolar crest height (ACH) loss and mandibular bone mass estimated by digital panoramic radiography and cone-beam computed tomography (CBCT). Material and methods: We studied 315 patients (43.2% [n = 136] men and 56.8% [n = 179] women) with mean age of 36.6 ± 5.3 (range 21-30 years (16.2%), range 31-46 years (83.8%); 9% (n = 71) were smokers (>10 cig./day). A mean of 13.0 ± 2.0 mandibular teeth were present: 37.5% of patients had 6-12 teeth and 62.5% 13-16 teeth. We analyzed 315 digital panoramic radiographs (2D) and calculated the ACH, mandibular cortical width, and basal and alveolar bone gray level values. ACH and bone density were also measured on CBCT (3D) in the 110 patients scheduled for implantation. Results: In the univariate analysis, ACH loss was greater in older patients (P = 0.012) and in those with fewer mandibular teeth (P < 0.001) and showed a relationship with tobacco consumption that was close to significant (P = 0.079). In the multivariate analysis, the number of mandibular teeth (P < 0.001) and tobacco consumption (P = 0.048) were significantly associated with ACH. Alveolar and basal bone densities were associated, respectively, with number of mandibular teeth (P = 0.012) and cortical width (P = 0.030). Conclusion: In a Caucasian population aged 21-46 years, tobacco consumption was significantly associated with ACH loss. However, ACH loss showed no significant relationship with mandibular bone mass estimated either as mandibular cortical width index or bone density on digital panoramic radiographs or as bone density on CBCT. ACH loss was a local event independent of mandibular bone mass status. [ABSTRACT FROM AUTHOR]