Influence of gender on periodontal outcomes: A retrospective analysis of eight randomized clinical trials.

AIMS: To explore the influence of gender on periodontal treatment outcomes in a dataset of eight RCTs conducted in Brazil, United States, and Germany. METHODS: Clinical parameters were compared between men and women with stages III/IV grades B/C generalized periodontitis at baseline and 1-year post-therapy, including scaling and root planing with or without antibiotics. RESULTS: Data from 1042 patients were analyzed. Men presented a tendency towards higher probing depth (p = .07, effect size = 0.11) and clinical attachment level (CAL) than women at baseline (p = .01, effect size = 0.16). Males also presented statistically significantly lower CAL gain at sites with CAL of 4-6 mm at 1-year post-therapy (p = .001, effect size = 0.20). Among patients with Grade B periodontitis who took antibiotics, a higher frequency of women achieved the endpoint for treatment (i.e., ≤4 sites PD ≥5 mm) at 1 year than men (p < .05, effect size = 0.12). CONCLUSION: Men enrolled in RCTs showed a slightly inferior clinical response to periodontal therapy in a limited number of sub-analyses when compared to women. These small differences did not appear to be clinically relevant. Although gender did not dictate the clinical response to periodontal treatment in this population, our findings suggest that future research should continue to explore this topic.

In-vitro biofilm removal from TiUnite® implant surface with an air polishing and two different plasma devices.

BACKGROUND: We investigated the efficacy of two different cold atmospheric pressure jet plasma devices (CAP09 and CAPmed) and an air polishing device with glycine powder (AP) either applied as monotherapies or combined therapies (AP + CAP09; AP + CAPmed), in microbial biofilm removal from discs with anodised titanium surface. METHODS: Discs covered with 7-day-old microbial biofilm were treated either with CAP09, CAPmed, AP, AP + CAP09 or AP + CAPmed and compared with negative and positive controls. Biofilm removal was assessed with flourescence and electron microscopy immediately after treatment and after 5 days of reincubation of the treated discs. RESULTS: Treatment with CAP09 or CAPmed did not lead to an effective biofilm removal, whereas treatment with AP detached the complete biofilm, which however regrew to baseline magnitude after 5 days of reincubation. Both combination therapies (AP + CAP09 and AP + CAPmed) achieved a complete biofilm removal immediately after cleaning. However, biofilm regrew after 5 days on 50% of the discs treated with the combination therapy. CONCLUSION: AP treatment alone can remove gross biofilm immediately from anodised titanium surfaces. However, it did not impede regrowth after 5 days, because microorganisms were probably hidden in holes and troughs, from which they could regrow, and which were inaccessible to AP. The combination of AP and plasma treatment probably removed or inactivated microorganisms also from these hard to access spots. These results were independent of the choice of plasma device.

Effect of quadrantwise versus full-mouth subgingival instrumentation on clinical and microbiological parameters in periodontitis patients: A randomized clinical trial.

AIM: This study evaluated the efficacy of quadrantwise subgingival instrumentation (Q-SI) versus one-stage full-mouth subgingival instrumentation (FM-SI) on probing depth and periodontal pathogen reduction over a 6-month follow-up period, as well as whether baseline periodontal pathogens influenced the impact of periodontal treatment protocols on outcomes. METHODS: Patients with periodontitis were randomized to receive Q-SI (n = 43) or FM-SI (n = 45). Patients were instructed and motivated to maintain optimal oral hygiene during the treatment sessions. Clinical (probing pocket depth [PPD], clinical attachment loss [CAL], and bleeding on probing [BOP]) and periodontal pathogens were assessed at baseline and after 30, 90, and 180 days. Total bacterial load and periodontal pathogens were analysed via real-time PCR. RESULTS: At the 6-month follow-up, the median PPD decreased from 4.8 mm (interquartile range [IQR]: 4.3-5.2) to 2.6 mm (IQR: 2.3-2.9) in FM-SI patients and from 4.7 mm (IQR: 4.1-5.2) to 3.2 mm (IQR: 2.4-3.5) in Q-SI patients (p < .001). At 6 months, FM-SI was more effective at reducing the median proportions of Porphyromonas gingivalis (Pg), Aggregatibacter actinocomyctemcomitans, and Tannerella forsythia (Tf) (p < .001 for each value). Multilevel linear regression analysis demonstrated that high baseline PPD (p = .029), Pg (p = .014), and Tf (p < .001) levels and the FM-SI protocol (p < .001) were statistically significant predictors of PPD reduction at 6 months. Furthermore, PPD reduction was significantly greater in the FM-SI group when lower baseline Pg levels were detected. CONCLUSION: The FM-SI was more effective than the Q-SI in reducing the mean PPD and number of periodontal pathogens in periodontitis patients over a 6-month follow-up period. Higher baseline PPD and Pg levels had a negative impact on PPD reduction at 6 months after FM-SI.

Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.

INTRODUCTION: Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host-pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose-response trial is necessary to assess the potential harm of this drug in this new indication. METHODS AND ANALYSIS: Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05033808.

Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport.

Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.

On- and off-target effects of paired CRISPR-Cas nickase in primary human cells.

Undesired on- and off-target effects of CRISPR-Cas nucleases remain a challenge in genome editing. While the use of Cas9 nickases has been shown to minimize off-target mutagenesis, their use in therapeutic genome editing has been hampered by a lack of efficacy. To overcome this limitation, we and others have developed double-nickase-based strategies to generate staggered DNA double-strand breaks to mediate gene disruption or gene correction with high efficiency. However, the impact of paired single-strand nicks on genome integrity has remained largely unexplored. Here, we developed a novel CAST-seq pipeline, dual CAST, to characterize chromosomal aberrations induced by paired CRISPR-Cas9 nickases at three different loci in primary keratinocytes derived from patients with epidermolysis bullosa. While targeting COL7A1, COL17A1, or LAMA3 with Cas9 nucleases caused previously undescribed chromosomal rearrangements, no chromosomal translocations were detected following paired-nickase editing. While the double-nicking strategy induced large deletions/inversions within a 10 kb region surrounding the target sites at all three loci, similar to the nucleases, the chromosomal on-target aberrations were qualitatively different and included a high proportion of insertions. Taken together, our data indicate that double-nickase approaches combine efficient editing with greatly reduced off-target effects but still leave substantial chromosomal aberrations at on-target sites.

Dmrt1 is the only male pathway gene tested indispensable for sex determination and functional testis development in tilapia.

Sex is determined by multiple factors derived from somatic and germ cells in vertebrates. We have identified amhy, dmrt1, gsdf as male and foxl2, foxl3, cyp19a1a as female sex determination pathway genes in Nile tilapia. However, the relationship among these genes is largely unclear. Here, we found that the gonads of dmrt1;cyp19a1a double mutants developed as ovaries or underdeveloped testes with no germ cells irrespective of their genetic sex. In addition, the gonads of dmrt1;cyp19a1a;cyp19a1b triple mutants still developed as ovaries. The gonads of foxl3;cyp19a1a double mutants developed as testes, while the gonads of dmrt1;cyp19a1a;foxl3 triple mutants eventually developed as ovaries. In contrast, the gonads of amhy;cyp19a1a, gsdf;cyp19a1a, amhy;foxl2, gsdf;foxl2 double and amhy;cyp19a1a;cyp19a1b, gsdf;cyp19a1a;cyp19a1b triple mutants developed as testes with spermatogenesis via up-regulation of dmrt1 in both somatic and germ cells. The gonads of amhy;foxl3 and gsdf;foxl3 double mutants developed as ovaries but with germ cells in spermatogenesis due to up-regulation of dmrt1. Taking the respective ovary and underdeveloped testis of dmrt1;foxl3 and dmrt1;foxl2 double mutants reported previously into consideration, we demonstrated that once dmrt1 mutated, the gonad could not be rescued to functional testis by mutating any female pathway gene. The sex reversal caused by mutation of male pathway genes other than dmrt1, including its upstream amhy and downstream gsdf, could be rescued by mutating female pathway gene. Overall, our data suggested that dmrt1 is the only male pathway gene tested indispensable for sex determination and functional testis development in tilapia.

ACES: A new framework for the application of the 2018 periodontal status classification scheme to epidemiological survey data.

AIM: To propose a framework for consistently applying the 2018 periodontal status classification scheme to epidemiological surveys (Application of the 2018 periodontal status Classification to Epidemiological Survey data, ACES). PROPOSED FRAMEWORK: We specified data requirements and workflows for either completed or planned epidemiological surveys, utilizing commonly collected measures of periodontal status (clinical attachment levels [CAL], probing depths, bleeding on probing), as well as additional necessary variables for the implementation of the 2018 periodontal status classification (tooth loss due to periodontitis and complexity factors). Following detailed instructions and flowcharts, survey participants are classified as having periodontal health, gingivitis or periodontitis. Rates of edentulism must also be reported. In cases of periodontitis, instructions on how to compute the stage and extent are provided. Assessment of grade can be derived from CAL measurements (or from radiographic alveolar bone loss data) in relation to root length and the participant's age. CONCLUSIONS: ACES is a framework to be used in epidemiological studies of periodontal status that (i) have been completed, and in which stage and grade according to the 2018 classification are inferred retroactively, or (ii) are being planned. Consistent use of the proposed comprehensive approach will facilitate the comparability of periodontitis prevalence estimates across studies.

Splicing Modulation via Antisense Oligonucleotides in Recessive Dystrophic Epidermolysis Bullosa.

Antisense oligonucleotides (ASOs) represent an emerging therapeutic platform for targeting genetic diseases by influencing various aspects of (pre-)mRNA biology, such as splicing, stability, and translation. In this study, we investigated the potential of modulating the splicing pattern in recessive dystrophic epidermolysis bullosa (RDEB) patient cells carrying a frequent genomic variant (c.425A > G) that disrupts splicing in the COL7A1 gene by using short 2'-O-(2-Methoxyethyl) oligoribo-nucleotides (2'-MOE ASOs). COL7A1-encoded type VII collagen (C7) forms the anchoring fibrils within the skin that are essential for the attachment of the epidermis to the underlying dermis. As such, gene variants of COL7A1 leading to functionally impaired or absent C7 manifest in the form of extensive blistering and wounding. The severity of the disease pattern warrants the development of novel therapies for patients. The c.425A > G variant at the COL7A1 exon 3/intron 3 junction lowers the efficiency of splicing at this junction, resulting in non-functional C7 transcripts. However, we found that correct splicing still occurs, albeit at a very low level, highlighting an opportunity for intervention by modulating the splicing reaction. We therefore screened 2'-MOE ASOs that bind along the COL7A1 target region ranging from exon 3 to the intron 3/exon 4 junction for their ability to modulate splicing. We identified ASOs capable of increasing the relative levels of correctly spliced COL7A1 transcripts by RT-PCR, sqRT-PCR, and ddPCR. Furthermore, RDEB-derived skin equivalents treated with one of the most promising ASOs exhibited an increase in full-length C7 expression and its accurate deposition along the basement membrane zone (BMZ).

Turnover of sex chromosomes in the Lake Tanganyika cichlid tribe Tropheini (Teleostei: Cichlidae).

Sex chromosome replacement is frequent in many vertebrate clades, including fish, frogs, and lizards. In order to understand the mechanisms responsible for sex chromosome turnover and the early stages of sex chromosome divergence, it is necessary to study lineages with recently evolved sex chromosomes. Here we examine sex chromosome evolution in a group of African cichlid fishes (tribe Tropheini) which began to diverge from one another less than 4 MYA. We have evidence for a previously unknown sex chromosome system, and preliminary indications of several additional systems not previously reported in this group. We find a high frequency of sex chromosome turnover and estimate a minimum of 14 turnovers in this tribe. We date the origin of the most common sex determining system in this tribe (XY-LG5/19) near the base of one of two major sub-clades of this tribe, about 3.4 MY ago. Finally, we observe variation in the size of one sex-determining region that suggests independent evolution of evolutionary strata in species with a shared sex-determination system. Our results illuminate the rapid rate of sex chromosome turnover in the tribe Tropheini and set the stage for further studies of the dynamics of sex chromosome evolution in this group.

Disruption of Zar1 leads to arrested oogenesis by regulating polyadenylation via Cpeb1 in tilapia (Oreochromis niloticus).

Oogenesis is a complex process regulated by precise coordination of multiple factors, including maternal genes. Zygote arrest 1 (zar1) has been identified as an ovary-specific maternal gene that is vital for oocyte-to-embryo transition and oogenesis in mouse and zebrafish. However, its function in other species remains to be elucidated. In the present study, zar1 was identified with conserved C-terminal zinc finger domains in Nile tilapia. zar1 was highly expressed in the ovary and specifically expressed in phase I and II oocytes. Disruption of zar1 led to the failed transition from oogonia to phase I oocytes, with somatic cell apoptosis. Down-regulation and failed polyadenylation of figla, gdf9, bmp15 and wee2 mRNAs were observed in the ovaries of zar1-/- fish. Cpeb1, a gene essential for polyadenylation that interacts with Zar1, was down-regulated in zar1-/- fish. Moreover, decreased levels of serum estrogen and increased levels of androgen were observed in zar1-/- fish. Taken together, zar1 seems to be essential for tilapia oogenesis by regulating polyadenylation and estrogen synthesis. Our study shows that Zar1 has different molecular functions during gonadal development by the similar signaling pathway in different species.

Complement C3 as a potential drug target in periodontitis: Evidence from the cis-Mendelian randomization approach.

AIM: Evidence from a Phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. Using drug-target Mendelian randomization (MR), we investigated whether genetically proxied C3 inhibition alters the risk of periodontitis. MATERIALS AND METHODS: We used multiple 'cis' instruments from the vicinity of the encoding loci of C3. Instrument selection was restricted to the drug target encoding loci (chromosome 19; 6,677,715-6,730,573 (GRCh37/hg19)). We selected three uncorrelated single-nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) that were associated with serum C3 levels (p value <1 × 10-4 ) from a genome-wide association study (GWAS) of 5368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis to estimate the odds ratio (OR) of the genetically proxied inhibition of C3 in relation to periodontitis. RESULTS: MR analysis revealed that the inhibition of C3 reduces the odds of periodontitis (OR 0.91 per 1 standard deviation reduction in C3; 95% confidence interval 0.87-0.96, p value = .0003). CONCLUSIONS: Findings from our MR analysis suggest a potential protective effect of C3 blockade against periodontitis.

Serum lipoprotein subfractions are associated with the periodontal status: Results from the population-based cohort SHIP-TREND.

AIM: To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1 H-NMR) spectroscopy with periodontitis and tooth loss. MATERIALS AND METHODS: A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1 H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing. RESULTS: While only spurious associations between lipoprotein levels from conventional blood tests were found-that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1 H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity. CONCLUSIONS: Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.

Interdental cleaning aids are beneficial for oral health at 7-year follow-up: Results from the Study of Health in Pomerania (SHIP-TREND).

AIM: To estimate association between the use of interdental cleaning aids (IDAs) and type on 7-year follow-up levels of interdental plaque, interdental gingival inflammation, interdental periodontitis severity, the number of interdental sound surfaces and the number of missing teeth in a population-based cohort study. MATERIALS AND METHODS: We used 7-year follow-up data of 2224 participants from the Study of Health in Pomerania (SHIP-TREND). We applied generalized linear and ordinal logistic models, adjusting for confounding and selection bias using inverse probability treatment weighting and multiple imputation. RESULTS: Flossers were 32% less likely to have higher interdental plaque (iPlaque) levels than non-users of IDAs (odds ratio [OR] = 0.68; 95% confidence interval [CI]: 0.50-0.94); flossing resulted in 5% lower means of iPlaque. Effects on interdental bleeding on probing (iBOP), mean interdental probing depths and mean interdental clinical attachment levels were direction-consistent but statistically non-significant. Interdental brushing was associated with lower follow-up levels for interdental plaque (OR = 0.73; 95% CI: 0.57-0.93) and iBOP (OR = 0.69; 95% CI: 0.53-0.89). IDAs were more effective in reducing iPlaque in participants with periodontitis, whereas iBOP reduction was more pronounced in participants with no or mild periodontitis. The analyses did not suggest that the use of IDAs affected caries. Finally, applying change score analyses, flossing reduced tooth loss incidence (incidence rate ratio [IRR] = 0.71) compared with non-users of IDAs. CONCLUSIONS: Recommending flossing and interdental brushing in dental practices represents an approach to the prevention of gingivitis and consequently periodontitis.

Systematic review and meta-analysis of randomized controlled trials evaluating the efficacy of non-surgical periodontal treatment in patients with concurrent systemic conditions.

OBJECTIVE: To conduct a systematic review of the published scientific evidence to evaluate the efficacy of nonsurgical periodontal therapy (NSPT) in treating periodontitis in patients with concurrent systemic conditions (diabetes, CVD, erectile dysfunction, chronic kidney disease, rheumatoid arthritis, polycystic ovarian syndrome, obesity, pregnancy). We hypothesised that NSPT results in better periodontal outcomes when compared to untreated controls after follow-up. MATERIALS AND METHODS: A systematic search (PUBMED/EMBASE) was conducted from 1995 to 2023 to identify randomised controlled trials (RCTs) with a minimum follow-up of 3 months. The primary outcome was the difference in mean probing depth (PD), and the secondary outcomes were mean clinical attachment loss (CAL), percentage of sites with PD ≤ 3 mm (%PD ≤ 3 mm) and percentage of sites with bleeding on probing (%BOP) between the treated and untreated control group in patients with comorbidities. RESULTS: The electronic search resulted in 2,403 hits. After removing duplicates, 1,565 titles and abstracts were screened according to the eligibility criteria, resulting in 126 articles for full-text screening. Following this, 44 studies were analysed. Restricting to studies with low bias or some concerns, NSPT group demonstrated a 0.55 mm lower mean PD (95%CI: -0.69; -0.41) after 3 months compared to the control group. CONCLUSION: Compared to the untreated controls, NSPT notably reduced mean PD, mean CAL, and %BOP while increasing %PD ≤ 3 mm in patients with concurrent systemic conditions. These findings suggest that NSPT is also an effective procedure in managing periodontitis in patients with concurrent systemic conditions. TRIAL REGISTRATION: This systematic review was registered under the protocol registration number CRD42021241517/PROSPERO.

Periodontitis and systemic inflammation as independent and interacting risk factors for mortality: evidence from a prospective cohort study.

BACKGROUND: Recent studies have highlighted the role of low-grade systemic inflammation in linking periodontitis to cardiovascular disease (CVD) outcomes, but many aspects remain unclear. This study examines the independent and reciprocal associations of periodontitis and low-grade systemic inflammation with all-cause and CVD mortality in a large-scale cohort. METHODS: A total of 3047 participants from the prospective, population-based Study of Health in Pomerania (SHIP-START) were followed for a period of 13.0 ± 2.4 years. For the association between various inflammation/periodontitis measures and mortality, hazard ratios (HRs) were obtained from covariate-adjusted Cox proportional hazards models. Interactions were analysed in joint models: on the multiplicative scale, HRs were reported and on the additive scale, relative excess risks due to interaction (RERI) were calculated. Subject and variable-specific interval records were used to account for time-varying exposures and covariates. RESULTS: During the observation period, 380 (12.5%) individuals died from CVD (n = 125) or other causes (n = 255). All markers of periodontitis and inflammation showed apparent associations with all-cause mortality (HRs per SD-increase: mean PPD: 1.068 (95% confidence interval (CI): 0.988-1.155), mean CAL: 1.205 (95% CI: 1.097-1.323), missing teeth: 1.180 (95% CI: 1.065-1.307), periodontitis score: 1.394 (95% CI: 1.202-1.616), leukocytes: 1.264 (95% CI: 1.163-1.374), fibrinogen: 1.120 (95% CI: 1.030-1.218), CRP: 1.231 (95% CI: 1.109-1.366), inflammation score: 1.358 (95% CI: 1.210-1.523)). For CVD mortality, all PPD related variables showed significant associations. Interaction modelling revealed some variation with respect to mortality type and exposure combinations. On the additive scale, RERIs for periodontitis score and inflammation score implied 18.9% and 27.8% excess mortality risk for all-cause and CVD mortality, respectively. On the multiplicative scale, the HRs for interaction were marginal. CONCLUSIONS: Both periodontitis and inflammation were significantly associated with all-cause mortality and CVD mortality. On the additive scale, a substantial excess risk was observed due to the interaction of periodontitis and inflammation, suggesting that the greatest treatment benefit may be achieved in patients with both periodontitis and high systemic inflammation. As periodontal therapy has been reported to also reduce systemic inflammation, the possibility of a reduction in CVD mortality risk by anti-inflammatory treatments, including periodontal interventions, seems worthy of further investigation.

Adult neural stem cells and neurogenesis are resilient to intermittent fasting.

Intermittent fasting (IF) is a promising strategy to counteract ageing shown to increase the number of adult-born neurons in the dentate gyrus of mice. However, it is unclear which steps of the adult neurogenesis process are regulated by IF. The number of adult neural stem cells (NSCs) decreases with age in an activation-dependent manner and, to counteract this loss, adult NSCs are found in a quiescent state which ensures their long-term maintenance. We aimed to determine if and how IF affects adult NSCs in the hippocampus. To identify the effects of every-other-day IF on NSCs and all following steps in the neurogenic lineage, we combined fasting with lineage tracing and label retention assays. We show here that IF does not affect NSC activation or maintenance and, that contrary to previous reports, IF does not increase neurogenesis. The same results are obtained regardless of strain, sex, diet length, tamoxifen administration or new-born neuron identification method. Our data suggest that NSCs maintain homeostasis upon IF and that this intervention is not a reliable strategy to increase adult neurogenesis.

The natural history of periodontal disease-Part 2: In populations with access to dental care: The Studies of Health in Pomerania (SHIP).

In this descriptive analysis of the 21-year follow-up data from the SHIP-START cohort and the 7-year follow-up data from the SHIP-TREND cohort, we report the progression of clinical attachment levels (CAL), age effects on CAL change, and a detailed description of CAL progression and remission. At baseline, 4307 and 4420 persons participated in SHIP-START and SHIP-TREND, respectively. At the final follow-up, 1181 and 2507 subjects were available for evaluation, respectively. In SHIP-START and SHIP-TREND participants, the mean CAL progressed by 0.04 and 0.02 mm/year, respectively. The older the participants were, the lower the average annual change in mean CAL (from 0.043 to 0.031 mm/year); annual tooth loss was 0.11-0.14 teeth/year. When participants were ranked according to their annual change in mean CAL, remission was more frequently observed in older subjects. To correctly understand the data, it is important to realize that selection bias due to dropouts during follow-up favored younger and more health-conscious persons. In addition, extraction of severely periodontally compromised teeth during follow-up biased the progression towards zero. Another explanation for these low CAL progression rates is that most sites had little or no change in CAL; this means that CAL progression was partly offset by CAL remission. Therefore, changes in mean CAL do not adequately describe the temporal course of periodontitis. Older age was not a risk factor for CAL progression in either cohort.

[Genetics in sports-muscle injuries]. / Genetische Faktoren bei Muskelverletzungen im Sport.

BACKGROUND: The human genome is the complete set of genetic instructions encoded in an individual's DNA. Genetics plays an important role in the development and progression of muscle injuries. Many genes are involved in muscle development, growth, and repair, and variations in these genes can affect an athlete's susceptibility to muscle injury. SPECIFIC GENES: Several genes have been linked to muscle injury, such as myostatin (MSTN), insulin-like growth factor 1 (IGF-1), and several collagen genes (COL). In addition to genes involved in muscle development, growth, and repair, genes involved in inflammation and pain signaling, such as tumor necrosis factor alpha (TNF-α), mu opioid receptor (OPRM1), and interleukin (IL) genes, may also play a role in the development and progression of muscle injury. GENETIC TESTS: Genetic testing can be a helpful tool in the prevention of muscle injuries in athletes. Testing for variations in genes associated with muscle development, repair, and growth, as well as collagen formation, can provide valuable information about an athlete's susceptibility to muscle injury. It is important to note that while genetic testing can provide valuable information for injury prevention, it is only one piece of the puzzle. Other factors such as an individual's training history, general health, and lifestyle habits also play a role in injury risk. Therefore, all injury prevention strategies should be individualized and based on a comprehensive assessment of all relevant factors.

ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia.

The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies.