The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay.

OBJECTIVES: Recent studies focused on angiogenesis in the pathophysiology of bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and identified geranylgeraniol (GGOH) as a feasible option for BP-ONJ therapy. This study investigated the influence of GGOH on microvessel sprouting after BP-incubation in vitro. MATERIALS AND METHODS: Ten experimental set-ups were randomly designed in an in vitro 3D-angiogenesis assay. Two groups included HUVEC cell spheroids with and without (±) GGOH substitution as controls and eight groups pairwise contained either clodronate or the nitrogen-containing bisphosphonates (N-BP) ibandronate, pamidronate, and zoledronate ± GGOH. The size of the cell spheroids including the outbranching sprouts (SpS) as well as the density (SpD) and length of the sprouts (SpL) were analyzed by a grid system after 0, 24, 48, and 72 h. RESULTS: For controls and NN-BP clodronate, no significant differences at any tested parameter and any point of measurement could be detected within the experimental set-ups ± GGOH (p each ≥0.05). For N-BP ibandronate, the experimental set-ups +GGOH showed a significantly increased SpS, SpD, and SpL after 48 and 72 h (p each ≤0.002) compared to the experimental set-ups -GGOH. For N-BPs pamidronate and zoledronate, the experimental set-ups + GGOH demonstrated a significantly increased SpS, SpD, and SpL after 24, 48, and 72 h (p each ≤0.001) compared to the experimental set-ups -GGOH. CONCLUSIONS: The strong negative influence of N-BPs on microvessel sprouting could be significantly reversed by GGOH. CLINICAL RELEVANCE: Since supportive therapeutic options for BP-ONJ are lacking, GGOH might be a promising substitute for BP-ONJ prevention and therapy.

Coping with perceived weight discrimination: testing a theoretical model for examining the relationship between perceived weight discrimination and depressive symptoms in a representative sample of individuals with obesity.

BACKGROUND: The association between obesity and perceived weight discrimination has been investigated in several studies. Although there is evidence that perceived weight discrimination is associated with negative outcomes on psychological well-being, there is a lack of research examining possible buffering effects of coping strategies in dealing with experiences of weight discrimination. The present study aims to fill that gap. We examined the relationship between perceived weight discrimination and depressive symptoms and tested whether problem-solving strategies and/or avoidant coping strategies mediated this effect. METHODS: Using structural equation modeling, we analyzed representative cross-sectional data of n=484 German-speaking individuals with obesity (BMI⩾30 kg m-2), aged 18 years and older. RESULTS: Results revealed a direct effect of perceived weight discrimination on depressive symptoms. Further, the data supported a mediational linkage for avoidant coping strategies, not for problem-solving strategies. Higher scores of perceived weight discrimination experiences were associated with both coping strategies, but only avoidant coping strategies were positively linked to more symptoms of depression. CONCLUSIONS: Perceived weight discrimination was associated with increased depressive symptoms both directly and indirectly through situational coping strategies. Avoidant coping has the potential to exacerbate depressive symptoms, whereas problem-solving strategies were ineffective in dealing with experiences of weight discrimination. We emphasize the importance of coping strategies in dealing with experiences of weight discrimination and the need to distinguish between using a strategy and benefiting from it without detriment.

Influence of CAD/CAM zirconia for implant-abutment manufacturing on gingival fibroblasts and oral keratinocytes.

OBJECTIVES: This study investigated the influence of three CAD/CAM zirconia ceramics for implant-abutment manufacturing on cell viability, migration ability, and cytotoxicity of human gingival fibroblasts (HGF) and oral keratinocytes (HOK) in vitro. MATERIALS AND METHODS: HGF and HOK were cultured on zirconia ceramic disks (VITA In-Ceram YZ, Ivoclar IPS e.max ZirCAD, Sirona inCoris ZI) and on control disks made of tissue culture polystyrene. Cell viability was analyzed by a MTT assay. Migration ability was detected by a scratch assay. A ToxiLight assay was used to analyze the influence of the tested zirconia ceramics on adenylate kinase (ADK) release and cytotoxicity. RESULTS: At MTT assay, HGF showed an increased cell viability compared to the control after 9 and 12 days for all ceramics (p each ≤0.0002) while HOK demonstrated a decreased cell viability after 9 and 12 days for all ceramics (p each ≤0.0003). At scratch assay, HGF exhibited for all ceramics decreased relative distances of the scratch wound compared to the control from 24 to 48 h (p each <0.0001) with exception of VITA In-Ceram YZ after 48 h. HOK showed increased distances compared to the control for all ceramics after 48 h (p each <0.0001). At ToxiLight assay, a minimal cytotoxicity of the tested materials could be detected. CONCLUSIONS: Overall, significant influences of the investigated CAD/CAM zirconia ceramics on HGF and HOK could be shown. CLINICAL RELEVANCE: The analyzed zirconia ceramics could influence oral soft-tissue cells that might affect the esthetic outcome after implant placement using CAD/CAM zirconia abutments.

Influence of mechanical compression on human periodontal ligament fibroblasts and osteoblasts.

OBJECTIVES: The aim of this study was to investigate and compare the changes in human periodontal ligament fibroblasts (HPdLFs) and osteoblasts (HOBs) after the application of compressive force (CF) at two different strengths in vitro. MATERIALS AND METHODS: HPdLF and HOB were exposed to CF with various strengths (5 and 10 %) using a Flexercell Compression Unit for 12 h in vitro. Viability was detected via 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) and apoptosis rate by transferase dUTP nick end labeling (TUNEL) assay. The gene expression of alkaline phosphatase (ALP), osteocalcin (OCN), osteoprotegerin (OPG), and receptor activator of NF-κB ligand (RANKL) was analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Osteopontin (OPN), matrix metalloproteinase-8 (MMP-8), and tissue inhibition of metalloproteinase-1 (TIMP-1) were quantified by an ELISA. RESULTS: Ten percent CF decreased viability, particularly in HOBs, but did not induce increased apoptosis. ALP gene expression increased the most after 5 % CF in HPdLFs and after 10 % CF in HOB. OCN was not affected by CF in either cell line. The highest RANKL/OPG ratio was measured after 5 % CF in both cell lines. OPN was upregulated in HOB by 5 %. HPdLFs showed an upregulation of MMP-8-synthesis and an increased MMP-8/TIMP-1 ratio. CONCLUSIONS: HOBs have a greater effect on bone remodeling through the upregulation of OPN, whereas HPdLFs facilitate orthodontic tooth movement by influencing the extracellular matrix via the MMP-8/TIMP-1 ratio. CLINICAL RELEVANCE: High CF in orthodontics should be avoided to prevent tissue damage, whereas moderate CF enables active tissue remodeling and tooth movement.

Isoprenoid geranylgeraniol: the influence on cell characteristics of endothelial progenitor cells after bisphosphonate therapy in vitro.

OBJECTIVES: Geranylgeraniol (GGOH) has been reported as a potential treatment option for bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ). The aim of this study was to analyze the effects of GGOH on endothelial progenitor cells (EPC) after bisphosphonate treatment in vitro. MATERIALS AND METHODS: EPC were incubated with different nitrogen (N-BPs: ibandronate, pamidronate, zoledronate) and a non-nitrogen-containing bisphosphonates (NN-BP: clodronate) with and without GGOH. Cell viability was measured by MTT and PrestoBlue assay. Migration ability was analyzed with a Boyden and Scratch assay. Apoptosis rates were determined by colony-forming, Tunel and ToxiLight assays. RESULTS: Negative effects of N-BPs on EPC were shown in all tests without GGOH. The substitution of GGOH demonstrated significantly increased cell viability (MTT: p each N-BP ≤0.004; PrestoBlue: p each N-BP <0.001) and migration ability (Boyden: p each N-BP <0.001; Scratch: p each N-BP <0.001). Concerning the apoptosis rates, increased EPC colony densities (p each N-BP ≤0.009), decreased numbers of apoptotic cells in the Tunel assay (p each N-BP <0.001), and a decreased adenylate kinase release in the ToxiLight assay (p each N-BP ≤0.03) were observed. For the clodronate-treated cells, no significant differences could be detected with or without GGOH in any assay (p each N-BP/NN-BP >0.05). CONCLUSIONS: GGOH cell treatment reversed the negative effects of bisphosphonates on EPC. CLINICAL RELEVANCE: These findings support the hypothesis that systemic or local GGOH treatment might lead to new therapeutic strategies for BP-ONJ.

Interdevice agreement of eight equivalent dental color measurement devices.

OBJECTIVES: The reproducibility of electronic color-measuring devices used in dentistry refers to the consistency of measurements of a single device and also that between identical devices. This in vitro study evaluated the short-term interdevice agreement of eight equivalent dental measurement devices. METHODS: The short-term repeatability of eight identical VITA Easyshade Advance color measurement devices was evaluated. Each device was used to quantify the Commission Internationale de l'Eclairage (CIE) L*a*b* color coordinates of ceramic disks, designed in accordance with guidelines set by the VITA Toothguide 3D-Master shade tab organization. Statistical analysis involved calculating the intraclass correlation coefficients (ICCs) and color differences (ΔE*) for corresponding measurements taken by the devices. In addition, the mean color difference from the mean (MCDM) was calculated for each color. RESULTS: All devices showed high ICCs for the color coordinates (L = 0.996, a = 0.993, b = 0.999). The ΔE* by shade ranged from 0.62 to 1.67. The MCDM by color-measuring device ranged from 0.11 to 0.23. CONCLUSION: This in vitro study showed that the color-measuring devices used were suitable for determining shade with high repeatability. CLINICAL RELEVANCE: The high interdevice agreement of the VITA Easyshade Advance means that dental professionals can use this device independently, without compromising the consistency and quality of color measurements.

Synchrotron-based X-ray tomographic microscopy for visualization of three-dimensional collagen matrices.

INTRODUCTION: Three-dimensional collagen matrices (3D-CMs) may be visualized by cumbersome reconstructions of serial sections. We report here on the method of synchrotron-based X-ray tomographic microscopy (SRXTM) to image 3D-CMs in native tissue probes. MATERIAL AND METHODS: SRXTM of 3D-CMs (mucoderm®, mucograft®) was performed at the TOMCAT beamline of the Swiss Light Source (SLS) at the Paul Scherrer Institute (Villigen, Switzerland). RESULTS: SRXTM combines the advantages of high-resolution scanning electron microscopy (SEM) imaging with the low-resolution reconstructions of micro-CT (µCT) imaging. It may be used to non-destructively visualize and analyze structures within the 3D-CMs without the need of serial sectioning and reconstruction. CONCLUSION: High-resolution SRXTM is a useful tool in analyzing the topology and morphometry of structures in 3D-CMs. The outcome justifies the efforts in sophisticated data processing. CLINICAL RELEVANCE: SRXTM may help to understand the clinical characteristics of 3D-CMs in more detail.

In vitro and in vivo characterization of porcine acellular dermal matrix for gingival augmentation procedures.

BACKGROUND AND OBJECTIVE: Recently, porcine acellular dermal matrix (PADM) has been proposed as a possible alternative to autogenous grafts in periodontal plastic surgery. The aim of the present study was to investigate the in vitro responses of four different oral cell lines cultured on a novel PADM. Furthermore, tissue reaction to PADM was evaluated histologically after subcutaneous implantation in mice. MATERIAL AND METHODS: Human gingival fibroblasts (HGF), human osteoblast-like cells, human umbilical vein endothelial cells and human oral keratinocytes (HOK) were cultured and transferred on to the PADM. A tissue culture polystyrene surface served as the control. The viability of all tested cell lines on PADM was measured by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay and PrestoBlue(®) reagent. The ToxiLight(®) assay was performed to analyze the effect of PADM on adenylate kinase release. PADM was implanted into nude mice subcutaneously and subjected to histological analysis after 21 d. RESULTS: Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assays, all tested cell lines cultured on PADM demonstrated a significant increase of viability compared to the control group (each p < 0.001) with the exception of HGF and HOK after 3 d (each p > 0.05). According to the PrestoBlue(®) analysis, all cell lines demonstrated a significant increase of viability compared to the control group at the particular points of measurement after 18 h (HGF p < 0.01; human osteoblast-like cells, human umbilical vein endothelial cells, HOK each p < 0.001). No significant cytotoxic effects of PADM on the tested cell lines could be observed, as assessed by changes in adenylate kinase release. Subcutaneous implantation of PADM into nude mice demonstrated good integration with surrounding tissues and significant revascularization of its collagen structure. CONCLUSION: Overall, the results suggest that PADM is a promising substitute for autogenous soft tissue grafts in periodontal surgery.

Bisphosphonates' antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay.

OBJECTIVES: Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is an adverse side effect of long-term bisphosphonate treatment. One theory of BP-ONJ etiology suggests a negative influence of these agents on angiogenesis and vascularization. This in vivo study analyzed the effects of bisphosphonates on angiogenesis in a 3D Matrigel assay. MATERIALS AND METHODS: Matrigel plugs were implanted into fifty 6-8-week-old female nude mice. Ten animals each were treated either with clodronate, ibandronate, pamidronate, zoledronate, or carrier solution as controls. The microvessel density (MVD), microvessel area (MVA), and microvessel size (MVS) in Matrigel plugs were analyzed after 21 days of treatment by immunohistochemistry and exemplary 3D microvascular corrosion castings. RESULTS: All bisphosphonates induced a statistically significant decrease of MVD (p each <0.001), whereby the nitrogen-containing bisphosphonates (N-BPs) demonstrated a clearly stronger effect than non-nitrogen-containing bisphosphonates (NN-BP) clodronate (control 166, clodronate 99, ibandronate 48, pamidronate 47, zoledronate 35 microvessels/mm(2)). Referring to MVA, similar results could be detected. MVS was significantly increased especially by ibandronate (103 %) compared to control group (p < 0.001). Scanning electron microscope scans of the corrosion castings confirmed these results. CONCLUSIONS: The stronger influence on MVD by N-BPs compared to the NN-BP clodronate may explain for the lack of BP-ONJ after treatment with NN-BPs. CLINICAL RELEVANCE: Ibandronate induced a strong increase of MVS. In combination with the reduced MVD, this could result only in a fractional reduced perfusion which might be an explanation for the lower occurrence of BP-ONJ in patients receiving ibandronate compared to patients receiving pamidronate or zoledronate.

Influence of CAD/CAM all-ceramic materials on cell viability, migration ability and adenylate kinase release of human gingival fibroblasts and oral keratinocytes.

OBJECTIVES: The aim of this study was to analyze the influence of four CAD/CAM all-ceramic materials on cell viability, migration ability and adenylate kinase (ADK) release of human gingival fibroblasts (HGF) and oral keratinocytes (HOK). MATERIALS AND METHODS: HGF and HOK were cultured on disc-shaped CAD/CAM all-ceramic materials (e.max CAD LT, e.max CAD HT, Empress CAD and Mark II) and on discs made of tissue culture polystyrene surface (TCPS) serving as control. Cell viability was analyzed by using an MTT assay, and migration ability was investigated by a scratch assay. A ToxiLight assay has been performed to analyze the effect of all-ceramic materials on ADK release and cell apoptosis. RESULTS: At MTT assay for HGF, no significant decrease of cell viability could be detected at all points of measurement (p each > 0.05), while HOK demonstrated a significant decrease in cell viability especially on Empress CAD and Mark II at each point of measurement (p each < 0.001). Scratch assay demonstrated an increased migration ability for HGF on e.max CAD HT, Empress CAD and Mark II (p each < 0.001), whereas HOK showed a significantly decreased migration ability on all tested materials at all points of measurement (between -36 % and -71 %; p each < 0.001). At ToxiLight assay, only small cytotoxic effects of the all-ceramic materials could be investigated. CONCLUSIONS: This study disclosed significant differences in cell viability and migration ability of HGF and HOK on CAD/CAM all-ceramic materials. CLINICAL RELEVANCE: CAD/CAM all-ceramic materials can influence oral cell lines responsible for soft tissue creation which may affect the esthetic outcome.

Who Benefited the Most? Effectiveness of a Lifestyle Intervention Against Cognitive Decline in Older Women and Men - Secondary Analysis of the AgeWell.de-trial.

INTRODUCTION: Differences between women and men matter in the prevalence and risk factors of dementia. We aimed to examine potential sex differences regarding the effectiveness by running a secondary analysis of the AgeWell.de trial, a cluster-randomized multicenter multi-domain lifestyle intervention to reduce cognitive decline. METHODS: Intention-to-treat analyses of women (n=433) and men (n=386) aged 60 to 77 years were used for models including interactions between intervention group allocation and sex followed by subgroup analysis stratified by sex on primary and secondary outcomes. Further, the same procedure was repeated for age groups (60-69 vs. 70-77) within sex-specific subgroups to assess the effectiveness in different age groups. TRIAL REGISTRATION: German Clinical Trials Register (ref. number: DRKS00013555). RESULTS: No differences were found between women and men in the effectiveness of the intervention on cognitive performance. However, women benefitted from the intervention regarding depressive symptoms while men did not. Health-related quality of life was enhanced for younger intervention participants (60-69 years) in both women and men. CONCLUSION: The AgeWell.de intervention was able to improve depressive symptoms in women and health-related quality of life in younger participants. Female participants between 60 and 69 years benefited the most. Results support the need of better individually targeted lifestyle interventions for older adults.

[Inpatient treatment of adolescents with acute alcohol intoxication: the tip of the iceberg?]. / Stationäre Behandlung von Jugendlichen mit akuter Alkoholintoxikation: Die Spitze des Eisbergs?

AIMS: This study assessed whether (i) adolescents treated in hospital for acute alcohol intoxication show different habitual drinking patterns from adolescents of the general population and whether (ii) predictors for repeated treatment can be identified. METHODS: A sample of adolescents who had undergone inpatient treatment for intoxication (clinical sample) comprised n=482 under 18-year-old subjects, who had additionally been surveyed within the context of the project "Hart am Limit" (HaLT) between 2008 and 2010 (mean age: 15.1 years, 44.4% girls). The population sample consisted of n=1 994 Bavarian students who had taken part in the European School Survey Project on Alcohol and other Drugs (ESPAD) in 2007 (mean age: 15.7 years; 54.4% girls). RESULTS: Within the clinical sample, gender differences in age, level of education and motivation to get drunk were found. Adolescents of the clinical sample were on average younger and had a higher level of education than adolescents in the general population sample. Although students in the clinical sample drank alcohol less often (2.8 vs. 5.0 times within the past 30 days), they drank more alcohol per occasion (36.4 g vs. 22.3 g pure alcohol per drinking day). Assessments by a third-party show that the risk of repeated inpatient treatment due to alcohol intoxication is positively associated with perceived psychosocial stress and negatively associated with perceived family support. CONCLUSIONS: A hospitalisation due to alcohol intoxication does not sufficiently indicate alarming habitual drinking behaviour. The risk of hospitalisation seems to depend on the drinking context and other factors of the drinking situation. Nevertheless, a sub-group of adolescents, who seem to display an elevated risk for intoxications, could be identified. It is for this sub-group, that supportive measures must be made available.

Gender-Specific Design and Effectiveness of Non-Pharmacological Interventions against Cognitive Decline - Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The number of people living with dementia worldwide is increasing rapidly. Preventive approaches constitute a promising strategy to counter the dementia epidemic, and growing numbers of lifestyle interventions are conducted around the globe. Gender differences with respect to modifiable risk factors for dementia have been reported, however, little is known about gender-specific effectiveness of lifestyle trials against cognitive decline and dementia. A systematic review and meta-analysis was conducted to assess evidence on gender-specific design and effectiveness of randomized controlled trials against cognitive decline. METHODS: Systematic literature searches were conducted in MEDLINE, PsycINFO, Web of Science, Cochrane Central and ALOIS. Studies assessing global and/or domain-specific cognitive function in older adults free from dementia were eligible for the systematic review. We assessed between-group effect sizes using random-effects meta-analysis. Methodological quality of included studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN)-checklist. RESULTS: The systematic review and meta-analysis included 34 and 31 studies, respectively. Effects of lifestyle-interventions on global cognition were non-significant overall (g = .27; 95% CI: -.01; .56) and in male subsamples (g = -.05; 95% CI: -.55; .45), and small for female subsamples (g = .38; 95% CI: .05; .72). Small beneficial effects were found for memory (overall: g = .38; 95% CI = .17; .59). Stratified by gender, significant effects were observed only in women (g = .39; 95% CI = .13; .65; men: g = .37; 95% CI: .00; .73). Aspects of gender in study design and conduct were discussed in a small minority of studies. Comparable results were observed for executive function and verbal fluency. Methodological quality was deemed high in 17.6% of studies, acceptable and low quality in 52.9% and 29.4%, respectively. DISCUSSION: We found evidence for small differences in the effectiveness of lifestyle interventions on global cognition and memory in favor of women. However, small numbers of trials 1) targeting men and 2) reporting gender-specific results for older adults with mild cognitive impairment warrant further attention. Assessing differences in modifiable risk factors for dementia in men and women and systematically addressing aspects of gender in trial conduction and recruitment in future studies might increase knowledge on gender-specific effectiveness of lifestyle trials against cognitive decline.

Are self-managed online interventions for depression effective in improving behavioral activation? A secondary analysis of a cluster-randomized controlled trial.

BACKGROUND: Online interventions can effectively improve depressive symptoms. They often include behavioral activation (BA) techniques, but research on the effects on behavioral activation is scarce. This study aims to examine short- and long-term effects of online interventions on behavioral activation in routine care. METHODS: This study is a secondary analysis of a pragmatic cluster-randomized controlled trial (@ktiv) with a sample of N = 647 GP patients with mild to moderate depression. The intervention group (IG) received treatment-as-usual (TAU) and adjunct access to an online intervention; the control group (CG) received TAU. BA was assessed in terms of the frequency and enjoyment of pleasant activities at baseline, after six weeks and after six months. Intention-to-treat analyses were performed via multilevel mixed linear regression. RESULTS: The frequency of pleasant activities was significantly higher in the IG than in the CG six months after baseline (t(1406) = 2.25, p = .024). The enjoyment of pleasant activities was significantly higher in the IG than in the CG both six weeks (t(1405) = 2.11, p = .035) and six months after baseline (t(1405) = 3.44, p = .001). Initial depressive symptoms significantly moderated the treatment effect on the enjoyment but not the frequency of pleasant activities. LIMITATIONS: BA measures have not been validated in a clinical context. CONCLUSIONS: GP patients with mild to moderate depressive symptoms profited from access to an online adjunct intervention in terms of improved behavioral activation. The findings emphasize the usefulness of online interventions as supportive options in mental health care.

Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro.

OBJECTIVES: Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is a side effect in patients being treated with bisphosphonates. The bisphosphonates most often associated with BP-ONJ are the highly potent nitrogen-containing bisphosphonates, e.g. pamidronate or zoledronate. In terms of BP-ONJ aetiology, several theories are being discussed: inhibition of bone remodelling, effect on soft tissues, and antiangiogenic effect of bisphosphonates. The aim of this in vitro study was to investigate the effect of different potent bisphosphonates on osteoblasts, fibroblasts and human umbilicord vein endothelial cells (HUVEC). MATERIALS AND METHODS: Three nitrogen-containing bisphosphonates (ibandronate, pamidronate and zoledronate) and one non-nitrogen-containing bisphosphonate (clodronate) were compared concerning their potency on apoptosis induction (tunel), cell viability (calcein assay) and migration potency (boyden chamber) on osteoblasts, fibroblasts and HUVEC. RESULTS: The nitrogen-containing bisphosphonates, particularly pamidronate and zoledronate, affect cell viability, cell migration and the induction of apoptosis of osteoblasts, fibroblasts and HUVEC. CONCLUSIONS: These results support the theory that BP-ONJ is a multifactorially caused disease because several cell lines of the oral cavity which are responsible for integrity and wound healing are negatively affected by nitrogen-containing bisphosphonates. Perioperative interruption of bisphosphonate application during dental surgical procedures--if possible--might be feasible to promote better wound healing.

Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells.

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is a side effect primarily in patients receiving highly potent nitrogen-containing bisphosphonates. The exact etiopathology is unknown. In addition to reduced bone remodeling, there may also be an impact on soft tissues. The impact of nitrogen- (ibandronate, pamidronate, zoledronate) and non-nitrogen-containing bisphosphonates (clodronate) on human umbilicord vein endothelial cells (HUVEC), fibroblasts and osteogenic cells was analyzed employing cell viability testing and a scratch wound assay. The impact on the cell morphology of vital-stained osteogenic cells was investigated by cell visualization (confocal laser scanning microscopy). Pamidronate and zoledronate had the greatest negative impact on all cell lines, whereas the impact of ibandronate and clodronate was less distinct. The effect of clodronate on HUVEC and fibroblasts was particularly marginal. BP-ONJ could be a multifactorial event with multicellular impairments. This might result in altered wound healing. The increased impact of the highly potent bisphosphonates, particularly on non-bone cells, may explain the higher occurrence of BP-ONJ.

Facial cutaneous squamous cell carcinoma - microscopic safety margins and their impact on developing local recurrences.

OBJECTIVES: Surgical excision remains the treatment of choice for facial cutaneous squamous cell carcinoma (cSCC) despite there being no generally accepted diameter of clear margins. Therefore, the aim of this study was to evaluate the impact of microscopic clear margins diameter (mCMD) with respect to the development of local recurrences (LR). MATERIALS AND METHODS: The medical records of 99 patients with a total of 142 cases of facial cSCC, who underwent surgical treatment between January 2010 and December 2015, were reviewed for demographic data and clinicopathological features. RESULTS: 100 cases were diagnosed as primary cSCC and 42 cases as secondary cSCC. Of these, nine (6.3%) developed LR. Mean time to LR was 20 months, with the cheek as the predominant site 55.5% (n = 5). Wound closure was either primary (56%) or secondary (44%), depending on the site. Although no significant correlation between mCMD and LR was found (rPearson = 0.029; rPearson = 0.015), >4.1 mm was shown to be a negative cut-off-value (horizontally and vertically) without LR (100% vs 0%). CONCLUSIONS: Based on these results, however descriptive they are, the authors consider histological confirmation of clear margins to be necessary for reducing the formation of LR. Thus, consistent testing and histopathological reporting, in a multicentered effort, are needed to further clarify the role of mCMD in the development of cSCC-LR.

Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Extensive bony metastases from facial metatypical basal cell carcinoma: a case report.

Metastatic basal cell carcinoma (BCC) is rare. We treated a 44-year-old woman with an extended facial metatypical BCC in whom staging showed no local or distant metastases, but one year after resection, we diagnosed a local recurrence. Re-staging, using a fludeoxyglucose positron emission tomography-computed tomogram, (FDG PET-CT) showed suspected accumulations of FDG in the whole axial skeleton. Bone punch biopsy examination confirmed extensive bony metastases, and after resection of the relapse, we began her on a systemic treatment with a Hedgehog-pathway inhibitor (vismodegib), which resulted in partial remission.

Is there an ideal way to close the donor site of radial forearm free flaps?

Radial forearm free flaps (RFFF) are the "workhorse" of reconstructive head and neck surgery, but have considerable morbidity at the donor site. The aim of this study was to review current publications about the incidence and type of morbidity and the different techniques used for closure of the site. We screened the MEDLINE database to find relevant papers using the terms "RFFF head and neck" and "RFFF donor site". Abstracts were filtered, and the full texts studied carefully. We found 1056 publications during the period 1982-2017 of which 389 were studied in full, and 39 studies were finally included in the review. We found four main methods of closure of the donor site: full-thickness skin grafts (FTSG); split-thickness skin grafts (STSG); modified techniques for raising the flap and closure of the wound by local flaps; and others (such as allografts, expanders, and vacuum bandages). For STSG and FTSG the preparation of the donor site seems to be a relevant factor. Special attention should be paid to the coverage of the flexor tendons. FTSG give better aesthetic results than STSG. Closure by local flaps may achieve primary closure of the donor site without a third surgical site, but the techniques are limited by the amount of tissue required at the site of the defect. The most common side effects are disorders of wound healing such as exposed tendons. To avoid exposure of the tendons, flexor tendons should be covered with muscle bellies when STSG are used. It is still not clear whether many other reported side effects (such as impairment of sensitivity) are induced by raising the flap or closing the donor site. There is an argument for closure of individual donor sites independently, but there is no one method of closure for all donor sites, because each has its specific disadvantages and complications.