Magnetic resonance imaging of the knee for chronological age estimation-a systematic review.

INTRODUCTION: Radiographs of the hand and teeth are frequently used for medical age assessment, as skeletal and dental maturation correlates with chronological age. These methods have been criticized for their lack of precision, and magnetic resonance imaging (MRI) of the knee has been proposed as a more accurate method. The aim of this systematic review is to explore the scientific and statistical evidence for medical age estimation based on skeletal maturation as assessed by MRI of the knee. MATERIALS AND METHODS: A systematic review was conducted that included studies published before April 2021 on living individuals between 8 and 30 years old, with presumptively healthy knees for whom the ossification stages had been evaluated using MRI. The correlation between "mature knee" and chronological age and the risk of misclassifying a child as an adult and vice versa was calculated. RESULTS: We found a considerable heterogeneity in the published studies -in terms of study population, MRI protocols, and grading systems used. There is a wide variation in the correlation between maturation stage and chronological age. CONCLUSION: Data from published literature is deemed too heterogenous to support the use of MRI of the knee for chronological age determination. Further, it is not possible to assess the sensitivity, specificity, negative predictive value, or positive predictive value for the ability of MRI to determine whether a person is over or under 18 years old. KEY POINTS: • There is an insufficient scientific basis for the use of magnetic resonance imaging of the knee in age determination by skeleton. • It is not possible to assess the predictive value of MRI of the knee to determine whether a person is over or under 18 years of age.

Experiences of living with fetal alcohol spectrum disorders: a systematic review and synthesis of qualitative data.

AIM: To identify and assess available evidence from qualitative studies exploring experiences of individuals living with fetal alcohol spectrum disorders (FASD) or those living with a child with FASD, as well as experiences of interventions aimed at supporting individuals with FASD and their families. METHOD: A systematic literature search was conducted in six electronic databases: PubMed, Embase, Cochrane Library, CINAHL, PsycINFO, and Scopus. Included studies were analysed using manifest content analysis. Methodological limitations and confidence in the evidence were assessed using a modified version of the Critical Appraisal Skills Programme and the Grading of Recommendations, Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research approach respectively. RESULTS: Findings from 18 studies show that individuals with FASD experience a variation of disabilities, ranging from somatic problems, high pain tolerance, destructive behaviour, hyperactivity, and aggressiveness, to social problems with friendship, school attendance, and maintenance of steady employment. Most studies reported parents' experiences with FASD; parenting was viewed as a lifelong engagement and that the whole family is isolated and burdened because of FASD. People with FASD feel that their difficulties affect their daily life in a limiting way and make them feel different from others. INTERPRETATION: From the perspective of primarily parents, individuals with FASD and their parents face many different difficulties, for which they need societal support. WHAT THIS PAPER ADDS: Individuals with fetal alcohol spectrum disorders (FASD) feel their difficulties make them different from others. Parents think of their parenting as a lifelong engagement. There is a shortage of studies investigating experiences of children with FASD. There is a shortage of studies investigating experiences of interventions given to individuals with FASD.

Ethical aspects of diagnosis and interventions for children with fetal alcohol Spectrum disorder (FASD) and their families.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) is an umbrella term covering several conditions for which alcohol consumption during pregnancy is taken to play a causal role. The benefit of individuals being identified with a condition within FASD remains controversial. The objective of the present study was to identify ethical aspects and consequences of diagnostics, interventions, and family support in relation to FASD. METHODS: Ethical aspects relating to diagnostics, interventions, and family support regarding FASD were compiled and discussed, drawing on a series of discussions with experts in the field, published literature, and medical ethicists. RESULTS: Several advantages and disadvantages in regards of obtaining a diagnosis or description of the condition were identified. For instance, it provides an explanation and potential preparedness for not yet encountered difficulties, which may play an essential role in acquiring much needed help and support from health care, school, and the social services. There are no interventions specifically evaluated for FASD conditions, but training programs and family support for conditions with symptoms overlapping with FASD, e.g. ADHD, autism, and intellectual disability, are likely to be relevant. Stigmatization, blame, and guilt are potential downsides. There might also be unfortunate prioritization if individuals with equal needs are treated differently depending on whether or not they meet the criteria for a specific condition. CONCLUSIONS: The value for the concerned individuals of obtaining a FASD-related description of their condition - for instance, in terms of wellbeing - is not established. Nor is it established that allocating resources based on whether individuals fulfil FASD-related criteria is justified, compared to allocations directed to the most prominent specific needs.

Annexin A5 inhibits atherogenic and pro-inflammatory effects of lysophosphatidylcholine.

OBJECTIVE: Atherosclerosis is an inflammatory condition, and rupture of atherosclerotic plaques is a major cause of cardiovascular disease (CVD). Lysophosphatidylcholine (LPC) is generated in low-density lipoprotein (LDL) during oxidation and/or enzymatic modification and has been implicated in atherosclerosis. Annexin A5 (ANXA5) is an antithrombotic and atheroprotective plasma protein. Here, we demonstrate novel pro-inflammatory and atherogenic properties of LPC, and inhibitory effects of ANXA5. METHODS: Endothelial cells and macrophages (differentiated from, THP-1 a monocytic cell line) were co-cultured. Expression of MMP-9 and OxLDL uptake by macrophages were studied by flow cytometry. The effect of LPC on leukotriene B4 (LTB4) synthesis in macrophages was studied by enzyme immunoassay (EIA). Chemotactic properties of LPC were investigated using a mouse intra-peritoneal recruitment model. RESULTS: Co-culture of macrophages and endothelial cells enhanced MMP-9 expression in both cell types. This effect was increased by LPC and diminished by ANXA5. Likewise, LPC induced LTB4 production by macrophages, whereas native LDL or phosphatidylcholine (PTC) had no effect. ANXA5 inhibited uptake of OxLDL in macrophages. LPC induced cell infiltration in vivo, as determined by increased cell count in mouse peritoneal exudates, and this effect was inhibited by ANXA5. CONCLUSIONS: ANXA5 could potentially play an important protective role in both atherogenesis and atherosclerotic plaque rupture by reducing pro-inflammatory effects of OxLDL and LPC as well as inhibiting OxLDL binding and uptake by macrophages. The possibility that ANXA5 could be developed into a novel therapy against CVD deserves further study.

The Effect of Domiciliary Professional Oral Care on Root Caries Progression in Care-Dependent Older Adults: A Systematic Review.

With care dependency, untreated root caries lesions (RCLs) and irregular dental visits are common. RCLs, if left untreated, could lead to pain, tooth loss, difficulties eating, and impact on general health. Therefore, there is a need for prevention and effective treatment for RCLs, and especially in those with care dependency. The aim of this systematic review was to investigate the effect of domiciliary professional oral care on root caries development and progression, in comparison with self-performed or nurse-assisted oral care. A literature search was conducted in four databases in November 2022. Two authors independently screened the literature throughout the review process. Five of the identified studies were found to be relevant. Four of these were assessed as having moderate risk of bias and were included in the review, while one study had high risk of bias and was excluded from further analyses. Due to heterogenicity of the included studies (and of the interventions and outcomes), no meta-analysis or synthesis without meta-analysis (SWiM) was performed. The participation of dental personnel performing mechanical plaque removal and fluoride, or chlorhexidine application seems beneficial for care-dependent older adults with risk of RCLs development and progression. However, future studies are needed.

How old are you? A systematic review investigating the relationship between age and mandibular third molar maturity.

INTRODUCTION AND OBJECTIVE: Radiographic evaluation of the maturity of mandibular third molars is a common method used for age estimation of adolescents and young adults. The aim of this systematic review was to examine the scientific base for the relationship between a fully matured mandibular third molar based on Demirjian's method and chronological age, in order to assess whether an individual is above or below the age of 18 years. METHODS: The literature search was conducted in six databases until February 2022 for studies reporting data evaluating the tooth maturity using Demirjian´s method (specifically stage H) within populations ranging from 8 to 30 years (chronological age). Two reviewers screened the titles and abstracts identified through the search strategy independently. All studies of potential relevance according to the inclusion criteria were obtained in full text, after which they were assessed for inclusion by two independent reviewers. Any disagreement was resolved by a discussion. Two reviewers independently evaluated the risk of bias using the assessment tool QUADAS-2 and extracted the data from the studies with low or moderate risk of bias. Logistic regression was used to estimate the relationship between chronological age and proportion of subjects with a fully matured mandibular third molar (Demirjian´s tooth stage H). RESULTS: A total of 15 studies with low or moderate risk of bias were included in the review. The studies were conducted in 13 countries and the chronological age of the investigated participants ranged from 3 to 27 years and the number of participants ranged between 208 and 5,769. Ten of the studies presented the results as mean age per Demirjian´s tooth stage H, but only five studies showed the distribution of developmental stages according to validated age. The proportion of subjects with a mandibular tooth in Demirjian´s tooth stage H at 18 years ranged from 0% to 22% among males and 0 to 16% in females. Since the studies were too heterogenous to perform a meta-analysis or a meaningful narrative review, we decided to refrain from a GRADE assessment. CONCLUSION: The identified literature does not provide scientific evidence for the relationship between Demirjian´s stage H of a mandibular third molar and chronologic age in order to assess if an individual is under or above the age of 18 years.

An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia.

OBJECTIVE: Therapeutic hypothermia is successfully used, for example, in cardiac surgery to protect organs from ischemia. Cardiosurgical procedures, especially in combination with extracorporeal circulation, and hypothermia itself are potentially prothrombotic. Despite the obvious need, the long half-life of antiplatelet drugs and thus the risk of postoperative bleedings have restricted their use in cardiac surgery. We describe here the design and testing of a unique recombinant hypothermia-controlled antiplatelet fusion protein with the aim of providing increased safety of hypothermia, as well as cardiac surgery. METHODS AND RESULTS: An elastin-mimetic polypeptide was fused to an activation-specific glycoprotein (GP) IIb/IIIa-blocking single-chain antibody. In silico modeling illustrated the sterical hindrance of a ß-spiral conformation of elastin-mimetic polypeptide preventing the single-chain antibody from inhibiting GPIIb/IIIa at 37°C. Circular dichroism spectra demonstrated reverse temperature transition, and flow cytometry showed binding to and blocking of GPIIb/IIIa at hypothermic body temperature (≤32°C) but not at normal body temperature. In vivo thrombosis in mice was selectively inhibited at hypothermia but not at 37°C. CONCLUSIONS: This is the first description of a broadly applicable pharmacological strategy by which the activity of a potential drug can be controlled by temperature. In particular, this drug steerability may provide substantial benefits for antiplatelet therapy.

Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha.

The proinflammatory mediator bradykinin (BK) is suggested to play an important role in the pathogenesis of various inflammatory diseases including periodontitis. In this study, BK per se stimulated interleukin-8 (IL-8) production in human gingival fibroblasts in vitro. Furthermore, BK upregulated the stimulatory effect of the cytokines IL-1beta and TNFalpha on the production of IL-8. The stimulatory effect of BK on the IL-1beta- or TNFalpha-stimulated IL-8 production was reduced in the presence of BK B2 receptor antagonist HOE 140, whereas the B1 receptor antagonist Lys-(des-arg9, Leu8)-BK had no effect. Similar to BK, the calcium ionophore A23187 also upregulated the stimulatory effect of IL-1beta and TNFalpha on IL-8 production. The protein kinase C (PKC) inhibitor bisindolylmaleimide, BIS, significantly reduced the stimulatory effect of BK on IL-1beta and TNFalpha increased IL-8 production but did not affect the production of IL-8 stimulated by cytokines alone. The specific p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 reduced IL-8 production stimulated by the combination of BK and IL-1beta as well as the IL-1beta-stimulated IL-8 production. In conclusion, this study shows that BK upregulates IL-1beta- and TNFalpha-stimulated IL-8 production via BK B2 receptor and that PKC signal pathway seems to be involved in the upregulation of the cytokine-induced IL-8 production in gingival fibroblasts. This stimulatory effect of BK on IL-8 production may contribute to the maintenance of the gingival inflammation and enhanced risk for destruction of gingival connective tissue.

Successful in vitro expansion and differentiation of cord blood derived CD34+ cells into early endothelial progenitor cells reveals highly differential gene expression.

Endothelial progenitor cells (EPCs) can be purified from peripheral blood, bone marrow or cord blood and are typically defined by a limited number of cell surface markers and a few functional tests. A detailed in vitro characterization is often restricted by the low cell numbers of circulating EPCs. Therefore in vitro culturing and expansion methods are applied, which allow at least distinguishing two different types of EPCs, early and late EPCs. Herein, we describe an in vitro culture technique with the aim to generate high numbers of phenotypically, functionally and genetically defined early EPCs from human cord blood. Characterization of EPCs was done by flow cytometry, immunofluorescence microscopy, colony forming unit (CFU) assay and endothelial tube formation assay. There was an average 48-fold increase in EPC numbers. EPCs expressed VEGFR-2, CD144, CD18, and CD61, and were positive for acetylated LDL uptake and ulex lectin binding. The cells stimulated endothelial tube formation only in co-cultures with mature endothelial cells and formed CFUs. Microarray analysis revealed highly up-regulated genes, including LL-37 (CAMP), PDK4, and alpha-2-macroglobulin. In addition, genes known to be associated with cardioprotective (GDF15) or pro-angiogenic (galectin-3) properties were also significantly up-regulated after a 72 h differentiation period on fibronectin. We present a novel method that allows to generate high numbers of phenotypically, functionally and genetically characterized early EPCs. Furthermore, we identified several genes newly linked to EPC differentiation, among them LL-37 (CAMP) was the most up-regulated gene.

Cell interactions between human gingival fibroblasts and monocytes stimulate the production of matrix metalloproteinase-1 in gingival fibroblasts.

BACKGROUND: Matrix metalloproteinase-1 (MMP-1) plays an important role in inflammatory diseases including periodontitis, which is characterized by tissue destruction and dense infiltration of mononuclear cells. OBJECTIVES: The aim of this study was to investigate the effect of cell interactions between human gingival fibroblasts and human monocytes on the production of MMP-1 in a coculture model. METHODS: The fibroblasts were cultured in either cell-to-cell contact with monocytes or in separated cocultures using a microporous membrane to prevent cell-to-cell contact. The mRNA expression of MMP-1 was analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and the protein levels of MMP-1 in the cell medium were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Coculturing gingival fibroblasts with monocytes in cell-to-cell contact increased the mRNA expression of MMP-1 in both fibroblasts and monocytes. The protein levels of MMP-1 increased in the culture media of the cocultures and correlated to the number of fibroblasts as well as to the number of monocytes. When fibroblasts were cultured with monocytes in separated cocultures, the mRNA expression and protein level of MMP-1 increased in the fibroblasts. In addition, treatment of fibroblasts with conditioned medium from monocytes also stimulated the production of MMP-1 in the fibroblasts. Moreover, the levels of the MMP-1 inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), increased in cocultures with cell-to-cell contact, but not in fibroblasts of separated cocultures. The glucocorticoid dexamethasone and the tetracycline doxycycline reduced the enhanced level of MMP-1 in the cocultures with cell-to-cell contact. CONCLUSION: The current study demonstrates that monocytes stimulate the production of MMP-1 in gingival fibroblasts by cell interactions, which may contribute to the maintenance of MMP-mediated tissue destruction in periodontitis.

Cell expression of MMP-1 and TIMP-1 in co-cultures of human gingival fibroblasts and monocytes: the involvement of ICAM-1.

Matrix metalloproteinase-1 (MMP-1) plays an important role in the degradation of collagen in inflammatory diseases. The aim of this study was to investigate the cellular expression of MMP-1 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in gingival fibroblasts co-cultured with monocytes and the possible mediating role of intercellular adhesion molecule-1 (ICAM-1). In co-cultures, the expression of MMP-1 and TIMP-1 increased in fibroblasts, but not in monocytes, although the number of MMP-1+ and TIMP-1+ adhered monocytes increased. Moreover, ICAM-1 expression in both fibroblasts and adhered monocytes increased. In the presence of an anti-ICAM-1 antibody, the expression of MMP-1 in fibroblasts decreased whereas the number of TIMP-1+ adhered monocytes increased. The p38 MAPK inhibitor SB203580 reduced MMP-1 expression in fibroblasts, as well as ICAM-1 expression in both fibroblasts and adhered monocytes. The results suggest that co-culture with monocytes enhances cellular expression of MMP-1 and TIMP-1 in gingival fibroblasts, and that the increased MMP-1 expression, in contrast to TIMP-1, is partly mediated by the adhesion molecule ICAM-1 and the p38 MAPK signal pathway.

Signal pathways involved in the production of MMP-1 and MMP-3 in human gingival fibroblasts.

Periodontitis is associated with enhanced production of cytokines, prostaglandins and matrix metalloproteinases (MMPs). The aim of this study was to investigate the production and regulation of MMP-1 and MMP-3 in human gingival fibroblasts challenged with the cytokines interleukin-lbeta (IL-1beta), tumor necrosis factor alpha (TNFalpha) or epidermal growth factor (EGF). The results showed that gingival fibroblasts constitutively produce MMP-1 and MMP-3, and that the cytokines IL-1beta, TNFalpha and EGF increase both MMP-1 and MMP-3 production in gingival fibroblasts. The upregulation by the cytokines was apparent at 8 h of incubation and increased thereafter continuously during 48 h of incubation. The upregulation of MMPs, induced by IL-1beta or TNFalpha, was reduced by the cyxlooxygenase-2 (COX-2) inhibitor NS-398, the p38 MAP-kinase inhibitor SB 203580, and the tyrosine kinase inhibitor herbimycin A. In addition, MMP-1 and MMP-3 production, induced by IL-1beta, TNFalpha or EGF, was strongly reduced by the presence of the glucocorticoid dexamethasone. Our findings demonstrate that the cytokines IL-1beta, TNFalpha and EGF, respectively, enhance both MMP-1 and MMP-3 production in human gingival fibroblasts, and that the signal pathways COX-2, MAP-kinases and tyrosine kinases are partly involved in the production of MMPs.