Regeneration of keratinized tissue around teeth and implants following coronal repositioning of alveolar mucosa with and without a connective tissue graft: an experimental study in dogs

Aim: To compare clinical and histological keratinized tissue formation around teeth and implants following coronal repositioning of alveolar mucosa with or without a connective tissue graft (CTG).Materials and Methods: In nine beagle dogs, the third and fourth premolars (P3 and P4) were extracted from one side of the maxilla. Three months after the tooth extraction, a full-thickness buccal flap was raised and two implants were placed in those healed areas. On the contra-lateral side, a buccal flap was also raised at the P3 and P4 areas. Before suturing, the dogs were randomly assigned to three study groups (control, non-keratinized tissue [NKT], and non-keratinized tissue CTG [NKT-CTG]). In the control group, the buccal flaps were re-positioned around the teeth (P3 and P4) on one side, and implants on the other side, presenting an adequate band of keratinized tissue (KT). For the NKT and NKT-CTG groups, this buccal KT was then excised. In the NKT group, the buccal flap without KT (alveolar mucosa) was re-positioned around the teeth and implants. In the NKT-CTG group, a CTG taken from the excised KT was sutured to the buccal alveolar mucosa and then both were re-positioned around the teeth and implants. The clinical height of the KT was measured at baseline and at 1, 2, and 3 months of healing. The animals were sacrificed at 3 months, at which point the KT height was measured histologically. Results: The control group presented normal healing with a band of KT surrounding the teeth and implants. In the NKT and NKT-CTG groups, a new KT band approximately 2 mm in height (measured clinically and histologically) spontaneously formed around all teeth, regardless of whether a CTG had been placed. In the NKT implant group, no new KT was observed (clinically or histologically). Around the implants in the NKT-CTG group, a small amount of KT was formed in just two of the six implants.Conclusions: After surgical excision of KT, spontaneous KT is formed around teeth but not around implants, regardless of the placement of a CTGS

Marginal changes at bone-level implants supporting fixed screw-retained partial implant prostheses with or without intermediate standardised abutments: 1-year results of a randomised controlled clinical trial

Objective: To compare marginal changes at bone- level implants restored with screw- retained implant prosthesis with or without intermediate standardised abutments, after 1 year of follow-up.Materials and Methods: Thirty- six partially edentulous patients received 72 implants. Each patient received 2 implants and a 2- to 4- unit screw- retained implant- prosthesis. The test group received implants consisting of a screw- retained prosthesis connected directly to the implant shoulder, while the prostheses in the control group were con-nected through a 3- mm standardised intermediate abutment. Clinical and radiological data were recorded at baseline and at 3, 6 and 12 months in follow-up visits.Results: At 12 months, the marginal bone loss was 0.17 ± 0.24 mm for the test group (19 patients) and 0.09 ± 0.15 mm for the control group (17 patients), with no statistically significant differences (p> .05). The mean probing pocket depth was 2.96 mm ± 0.46 for the test group and 2.86 ± 0.62 mm for the control group. The test and control groups showed bleeding on probing levels of 18.86 ± 14.12% and 13.73 ± 17.66%, re-spectively. All patients scored below 25% on the plaque index levels.Conclusions: Restoration of bone- level implants with fixed screw- retained partial prostheses with or without intermediate abutments presented similar radiographic and clinical outcomes after 1 yearS

κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine’s effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine’s effects on energy balanceThis research was funded from the Xunta de Galicia (R.N.: 2016-PG057; ML: 2016-PG068); Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (R.N.: RTI2018-099413-B-I00; C.D.: BFU2017-87721-P; M.L.: RTI2018-101840-B-I00); Atresmedia Corporación (RN and ML); Fundación BBVA (RN); “la Caixa” Foundation (ID 100010434), under the agreements LCF/PR/HR19/52160016 (R.N.) and LCF/PR/HR19/52160022 (M.L.); European Foundation for the Study of Diabetes (R.N.), ERC Synergy Grant-2019-WATCH- 810331 (R.N.) and Western Norway Regional Health Authority (Helse Vest RHF) (J.F.). P.S.-C. is the recipient of a fellowship from Xunta de Galicia (ED481B 2018/050). The CiMUS is supported by the Xunta de Galicia (2016-2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy

Celia’s encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.This work was supported by the Fundación Mutua Madrileña and by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (PI13/00314).S

Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress

Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in femalesThe research leading to these results has received funding from Xunta de Galicia (R.N.: 2015-CP080 and 2016-PG057; M.L.: 2015-CP079), MINECO co-funded by the FEDER Program of EU (R.N.: BFU2015-70664R; D.P.: SAF2016-77526-R; C.D.: BFU2017-87721; M.L.: SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016-2019, ED431G/05). L.L.-P. is a recipient of a fellowship from Xunta de Galicia (ED481A-2016/094); E.R.-P. is a recipient of a fellowship from MINECO (BES-2015-072743); A.E.-S. is a recipient of a fellowship from MINECO (FPI/BES-2016-077439); C.R. is a recipient of a fellowship from MINECO (FPU16/04582). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Development of a new preclinical model to study early implant loss: a validation study in the beagle dog

Objectives: To develop a new preclinical model to study early implant loss, where local infection conditions would impair the implant osseointegration. Materials and methods: Forty-eight smooth, 2.9-mm diameter experimental implants were placed in the mandible of 8 beagle dogs (3 in each side). In half of the animals (test group, n = 24 implants), the implants received ligatures around the implant-abutment connection. In the other half, no ligatures were placed (control group, n = 24 implants). Four weeks later, implants were extracted in a flapless approach and standard 3.3-mm diameter SLActive implants were placed into the same osteotomy site without any further drilling. Eight weeks after the second implantation, animals were sacrificed and analyzed in terms of implant survival. Results: After 8 weeks of healing, 4 implants were lost in the control group and 14 in the test group. This corresponded to a 17.4% of early implant loss in the control group and 58.3% in the test. Most of the early failures occurred within the first 5 weeks of healing. Conclusions: Implants placed in a pre-contaminated site present higher early loss than those placed in a non-contaminated site. This study represents a valid and robust preclinical model to study mechanisms and reduction of early implant loss as new technologies become available. Clinical relevance: Scientific rationale for the study: There is lack of animal models to study early implant loss. Thus, a proposal of a new model is presented. With the validation of this model, new technologies can be implemented to prevent early implant lossOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was sponsored by an ITI grant 1111_2015S

Adjunctive benefits of systemic metronidazole on non-surgical treatment of peri-implantitis. A randomized placebo-controlled clinical trial

Aim: To study clinical, radiographic, and microbiological outcomes after non-surgical therapy of peri-implantitis with or without adjunctive systemic metronidazole. Materials and Methods: A randomized placebo-controlled clinical trial was carried out in 32 subjects (62 implants) diagnosed with peri-implantitis. Implants received a mechanical non-surgical debridement session and systemic metronidazole or placebo. Clinical, radiographic, and microbiological outcomes were evaluated at baseline, 3, 6, and 12 months. Results: After 12 months, the test treatment resulted in significantly greater PPD reduction (2.53 vs. 1.02 mm) and CAL gain (2.14 vs. 0.53 mm) (p value <.05) in comparison with placebo. The test treatment also resulted in additional radiographic bone gain (2.33 vs. 1.13 mm) compared with placebo (p value <.05). There was a significantly greater decrease in Porphyromonas gingivalis, Tannerella forsythia, and Campylobacter rectus counts compared with the control group (p value <.05). At the end of follow-up, 56.3% of patients met the success criteria in the test group and 25% in the control group. Conclusions: The use of systemic metronidazole as an adjunct to non-surgical treatment of peri-implantitis resulted in significant additional improvements in clinical, radiographic, and microbiological parameters after 12 months of follow-up. This study is registered in ClinicalTrials.gov (NCT03564301)S

Evolution of invasive pneumococcal disease by serotype 3 in adults : a Spanish three-decade retrospective study

Background: Invasive pneumococcal disease due to serotype 3 (S3-IPD) is associated with high mortality rates and long-term adverse effects. The introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the Spanish paediatric immunisation programme has not led to a decrease in the adult S3-IPD. We aimed to analyse the incidence, clinical characteristics and genomics of S3-IPD in adults in Spain. Methods: Adult IPD episodes hospitalized in a Southern Barcelona hospital were prospectively collected (1994-2020). For genomic comparison, S3-IPD isolates from six Spanish hospitals (2008-2020) and historical isolates (1989-1993) were analysed by WGS (Illumina and/or MinION). Findings: From 1994 to 2020, 270 S3-IPD episodes were detected. When comparing pre-PCV (1994-2001) and late-PCV13 (2016-2020) periods, only modest changes in S3-IPD were observed (from 1.58 to 1.28 episodes per 100,000 inhabitants year). In this period, the incidence of the two main lineages shifted from 0.38 to 0.67 (CC180-GPSC12) and from 1.18 to 0.55 (CC260-GPSC83). The overall 30-day mortality remained high (24.1%), though a decrease was observed between the pre-PCV (32.4%; 95.0% CI, 22.0-45.0) and the late-PCV13 period (16.7%; 95.0% CI, 7.5-32.0) (p = 0.06). At the same time, comorbidities increased from 77.3% (95.0% CI, 65.0-86.0) to 85.7% (95.0% CI, 71.0-94.0) (p = 0.69). There were no differences in clinical characteristics or 30-day mortality between the two S3 lineages. Although both lineages were genetically homogeneous, the CC180-GPSC12 lineage presented a higher SNP density, a more open pan-genome, and a major presence of prophages and mobile genetic elements carrying resistance genes. Interpretation: Adult S3-IPD remained stable in our area over the study period despite PCV13 introduction in children. However, a clonal shift was observed. The decrease in mortality rates and the increase in comorbidities suggest a change in clinical management and overall population characteristics. The low genetic variability and absence of clinical differences between lineages highlight the role of the S3 capsule in the disease severity. Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) "PI18/00339", "PI21/01000", "INT22/00096", "FI22/00279", CIBER "CIBERES-CB06/06/0037", "CIBERINFEC-CB21/13/00009" and MSD grant "IISP 60168"