Cognitive Behavioral Program for the Prevention of Depression in At-Risk Adolescents: Isolating the Effects of Dose.

The current study estimated effects of intervention dose (attendance) of a cognitive behavioral prevention (CBP) program on depression-free days (DFD) in adolescent offspring of parents with a history of depression. As part of secondary analyses of a multi-site randomized controlled trial, we analyzed the complete intention-to-treat sample of 316 at-risk adolescents ages 13-17. Youth were randomly assigned to the CBP program plus usual care (n=159) or to usual care alone (n=157). The CBP program involved 8 weekly acute sessions and 6 monthly continuation sessions. Results showed that higher CBP program dose predicted more DFDs, with a key threshold of approximately 75% of a full dose in analyses employing instrumental variable methodology to control multiple channels of bias. Specifically, attending at more than 75% of acute phase sessions led to 45.3 more DFDs over the 9-month period post randomization, which accounted for over 12% of the total follow-up days. Instrument sets were informed by study variables and external data including weather and travel burden. In contrast, conventional analysis methods failed to find a significant dose-outcome relation. Application of the instrumental variable approach, which better controls the influence of confounding, demonstrated that higher CBP program dose resulted in more DFDs.

Weekly links among irritability and suicidal thoughts and behaviors in high-risk youth.

BACKGROUND: Previous studies demonstrate a link between irritability and suicidal thoughts and behaviors (STBs) in youth samples. However, they have mostly assessed irritability in community samples and as a largely dispositional (i.e. trait-like) construct. Thus, it remains unclear to what extent links between irritability and STBs reflect within-person processes of elevated risk in clinically meaningful time periods. METHODS: The present study used clinical data from 689 adolescents aged 12-19 years attending a total of 6,128 visits at a specialty Intensive Outpatient Program for depressed and suicidal youth to examine patterns in weekly assessments of irritability and STBs throughout treatment, including associations among trends and fluctuations departing from these trends via multilevel structural equation modeling. Youth completed self-report measures of irritability, depression, and STBs weekly as part of standard IOP clinical care. RESULTS: Overall, two-thirds of variance in weekly irritable mood was accounted for by between-person differences and the remaining portion by weekly fluctuations. After controlling for depression, during weeks when youth were more irritable they experienced increased STBs. Rates of change in irritability and STBs tended to track together at early stages of treatment, but these effects were generally accounted for by depression severity. CONCLUSIONS: Our results suggest that although changes in STBs are best accounted for by depression, irritability can be understood as a specific, proximal risk factor for youth STBs that exacerbates youth STBs in clinically informative timeframes above and beyond depression.

Testing the interpersonal theory of suicide in adolescents: A multi-wave longitudinal study.

BACKGROUND: Suicide is a major public health crisis among youth. Several prominent theories, including the Interpersonal Theory of Suicide (IPTS), aim to characterize the factors leading from suicide ideation to action. These theories are largely based on findings in adults and require testing and elaboration in adolescents. METHODS: Data were examined from high-risk 13-18-year-old adolescents (N = 167) participating in a multi-wave, longitudinal study; 63% of the sample exhibited current suicidal thoughts or recent behaviors (n = 105). The study included a 6-month follow-up period with clinical interviews and self-report measures at each of the four assessments as well as weekly smartphone-based assessments of suicidal thoughts and behaviors. Regression and structural equation models were used to probe hypotheses related to the core tenets of the IPTS. RESULTS: Feelings of perceived burdensomeness were associated with more severe self-reported suicidal ideation (b = 0.58, t(158) = 7.64, p < .001). Similarly, burdensomeness was associated with more frequent ideation based on weekly smartphone ratings (b = 0.11, t(1460) = 3.41, p < .001). Contrary to IPTS hypotheses, neither feelings of thwarted belongingness, nor interactions between burdensomeness and thwarted belongingness were significantly associated with ideation (ps > .05). Only elevated depression severity was associated with greater odds of suicide events (i.e., suicide attempts, psychiatric hospitalizations, and/or emergency department visits for suicide concerns) during the follow-up period (OR = 1.83, t(158) = 2.44, p = .01). No effect of acquired capability was found. CONCLUSIONS: Perceptions of burdensomeness to others reflect a critical risk factor for suicidal ideation among high-risk adolescents. Null findings with other IPTS constructs may suggest a need to adopt more developmentally sensitive models or measures of interpersonal and acquired capability risk factors for youth. Refining methods and theoretical models of suicide risk may help improve the identification of high-risk cases and inform clinical intervention.

Oxidized Phospholipids Regulate Tenocyte Function via Induction of Amphiregulin in Dendritic Cells.

Inflammation is a driving force of tendinopathy. The oxidation of phospholipids by free radicals is a consequence of inflammatory reactions and is an important indicator of tissue damage. Here, we have studied the impact of oxidized phospholipids (OxPAPC) on the function of human tenocytes. We observed that treatment with OxPAPC did not alter the morphology, growth and capacity to produce collagen in healthy or diseased tenocytes. However, since OxPAPC is a known modulator of the function of immune cells, we analyzed whether OxPAPC-treated immune cells might influence the fate of tenocytes. Co-culture of tenocytes with immature, monocyte-derived dendritic cells treated with OxPAPC (Ox-DCs) was found to enhance the proliferation of tenocytes, particularly those from diseased tendons. Using transcriptional profiling of Ox-DCs, we identified amphiregulin (AREG), a ligand for EGFR, as a possible mediator of this proliferation enhancing effect, which we could confirm using recombinant AREG. Of note, diseased tenocytes were found to express higher levels of EGFR compared to tenocytes isolated from healthy donors and show a stronger proliferative response upon co-culture with Ox-DCs, as well as AREG treatment. In summary, we identify an AREG-EGFR axis as a mediator of a DC-tenocyte crosstalk, leading to increased tenocyte proliferation and possibly tendon regeneration.

Early indicators of response to transdiagnostic treatment of pediatric anxiety and depression.

BACKGROUND: Pediatric anxiety and depression are prevalent, impairing, and highly comorbid. Available evidence-based treatments have an average response rate of 60%. One path to increasing response may be to identify likely non-responders midway through treatment to adjust course prior to completing an episode of care. The aims of this study, thus, were to identify predictors of post-intervention response assessing (a) mid-treatment symptom severity, (b) session-by-session treatment process factors, and (c) a model optimizing the combination of these. METHOD: Data were drawn from the treatment arm (N = 95, ages 8-16) of a randomized transdiagnostic intervention trial (Msessions = 11.2). Mid-point measures of youth- and parent-reported anxiety and depression were collected, and therapists rated homework completion, youth and parent engagement, and youth therapeutic alliance at each session. Logistic regression was used to predict response on the Clinical Global Impression Improvement Scale (CGI-I ≤2) rated by independent evaluators masked to treatment condition. RESULTS: Mid-point symptom measures were significant predictors of treatment response, as were therapist-ratings of youth and parent engagement, therapeutic alliance, and homework completion. Therapist ratings were significant when tested as mean ratings summing across the first eight sessions of treatment (all ps < .004) and at individual session points (all ps <0.05). A combined prediction model included youth-reported anxiety, parent-reported depression, youth engagement at Session 2, and parent engagement at Session 8. This model correctly classified 76.5% of youth as non-responders and 91.3% as responders at post-treatment (Nagelkerke R2 = .59, χ2 (4, 80) = 46.54, p < .001). CONCLUSION: This study provides initial evidence that response to transdiagnostic intervention for pediatric anxiety and depression may be reliably predicted by mid-point. These data may serve as foundational evidence to develop adaptive treatment strategies to personalize intervention, correct treatment course, and optimize outcomes for youth with anxiety and depression.

Bottom-Up Strategy to Forecast the Drug Location and Release Kinetics in Antitumoral Electrospun Drug Delivery Systems.

Electrospun systems are becoming promising devices usable for topical treatments. They are eligible to deliver different therapies, from anti-inflammatory to antitumoral. In the current research, polycaprolactone electrospun membranes loaded with synthetic and commercial antitumoral active substances were produced, underlining how the matrix-filler affinity is a crucial parameter for designing drug delivery devices. Nanofibrous membranes loaded with different percentages of Dacarbazine (the drug of choice for melanoma) and a synthetic derivative of Dacarbazine were produced and compared to membranes loaded with AuM1, a highly active Au-complex with low affinity to the matrix. AFM morphologies showed that the surface profile of nanofibers loaded with affine substances is similar to one of the unloaded systems, thanks to the nature of the matrix-filler interaction. FTIR analyses proved the efficacy of the interaction between the amidic group of the Dacarbazine and the polycaprolactone. In AuM1-loaded membranes, because of the weak matrix-filler interaction, the complex is mainly aggregated in nanometric domains on the nanofiber surface, which manifests a nanometric roughness. Consequently, the release profiles follow a Fickian behavior for the Dacarbazine-based systems, whereas a two-step with a highly prominent burst effect was observed for AuM1 systems. The performed antitumoral tests evidence the high-cytotoxic activity of the electrospun systems against melanoma cell lines, proving that the synthetic substances are more active than the commercial dacarbazine.

Endotenon-Derived Type II Tendon Stem Cells Have Enhanced Proliferative and Tenogenic Potential.

Tendon injuries caused by overuse or age-related deterioration are frequent. Incomplete knowledge of somatic tendon cell biology and their progenitors has hindered interventions for the effective repair of injured tendons. Here, we sought to compare and contrast distinct tendon-derived cell populations: type I and II tendon stem cells (TSCs) and tenocytes (TNCs). Porcine type I and II TSCs were isolated via the enzymatic digestion of distinct membranes (paratenon and endotenon, respectively), while tenocytes were isolated through an explant method. Resultant cell populations were characterized by morphology, differentiation, molecular, flow cytometry, and immunofluorescence analysis. Cells were isolated, cultured, and evaluated in two alternate oxygen concentrations (physiological (2%) and air (21%)) to determine the role of oxygen in cell biology determination within this relatively avascular tissue. The different cell populations demonstrated distinct proliferative potential, morphology, and transcript levels (both for tenogenic and stem cell markers). In contrast, all tendon-derived cell populations displayed multipotent differentiation potential and immunophenotypes (positive for CD90 and CD44). Type II TSCs emerged as the most promising tendon-derived cell population for expansion, given their enhanced proliferative potential, multipotency, and maintenance of a tenogenic profile at early and late passage. Moreover, in all cases, physoxia promoted the enhanced proliferation and maintenance of a tenogenic profile. These observations help shed light on the biological mechanisms of tendon cells, with the potential to aid in the development of novel therapeutic approaches for tendon disorders.

Activity and Selectivity of Novel Chemical Metallic Complexes with Potential Anticancer Effects on Melanoma Cells.

Human malignant melanoma cells from lymph node metastatic site (MeWo) were selected for testing several synthesized and purified silver(I) and gold(I) complexes stabilized by unsymmetrically substituted N-heterocyclic carbene (NHC) ligands, called L20 (N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide) and M1 (4,5-dichloro, N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide), having halogenide (Cl- or I-) or aminoacyl (Gly=N-(tert-Butoxycarbonyl)glycinate or Phe=(S)-N-(tert-Butoxycarbonyl)phenylalaninate) counterion. For AgL20, AuL20, AgM1 and AuM1, the Half-Maximal Inhibitory Concentration (IC50) values were measured, and all complexes seemed to reduce cell viability more effectively than Cisplatin, selected as control. The complex named AuM1 was the most active just after 8 h of treatment at 5 µM, identified as effective growth inhibition concentration. AuM1 also showed a linear dose and time-dependent effect. Moreover, AuM1 and AgM1 modified the phosphorylation levels of proteins associated with DNA lesions (H2AX) and cell cycle progression (ERK). Further screening of complex aminoacyl derivatives indicated that the most powerful were those indicated with the acronyms: GlyAg, PheAg, AgL20Gly, AgM1Gly, AuM1Gly, AgL20Phe, AgM1Phe, AuM1Phe. Indeed, the presence of Boc-Glycine (Gly) and Boc-L-Phenylalanine (Phe) showed an improved efficacy of Ag main complexes, as well as that of AuM1 derivatives. Selectivity was further checked on a non-cancerous cell line, a spontaneously transformed aneuploid immortal keratinocyte from adult human skin (HaCaT). In such a case, AuM1 and PheAg complexes resulted as the most selective allowing HaCaT viability at 70 and 40%, respectively, after 48 h of treatment at 5 µM. The same complexes tested on 3D MeWo static culture induced partial spheroid disaggregation after 24 h of culture, with almost half of the cells dead.

Increased burden of cardiovascular risk among youth suicide attempters.

BACKGROUND: Suicide and cardiovascular disease rank among the leading causes of disability and premature mortality worldwide. Young adult suicide attempters are at increased risk of mortality from cardiovascular disease even compared to those with major depressive disorder suggesting an increased burden of cardiovascular risk factors. We compared the cardiovascular risk burden between youth attempters and other high-risk individuals. METHODS: Participants were from the Collaborative Psychiatric Epidemiology Surveys (CPES), a U.S. population-based study, aged 18-30 years [suicide attempt (SA): n = 303; suicidal ideation (SI): n = 451; controls: n = 3671]; and psychiatric inpatients admitted for a SA (n = 38) or SI (n = 40) and healthy controls (n = 37) aged 15-30 years. We computed a cardiovascular risk score and high- and low-risk latent classes based on risk factors of high blood pressure, obesity, and smoking. RESULTS: Suicide attempters showed an increased cardiovascular risk score (CPES: B = 0.43, 95% confidence interval (CI) 0.31-0.54, p < 0.001; inpatient sample: B = 1.61, 95% CI 0.53-2.68, p = 0.004) compared to controls. They were also more likely to be classified in the high cardiovascular risk group (CPES: odds ratio (OR) 3.36, 95% CI 1.67-6.78, p = 0.001; inpatient sample: OR 9.89, 95% CI 1.38-85.39, p = 0.03) compared to those with SI (CPES: OR 1.15, 95% CI 0.55-2.39, p = 0.71; inpatient sample: OR 1.91, 95% CI 0.25-15.00, p = 0.53). CONCLUSIONS: Youth attempters show an increased burden for cardiovascular risk compared to other high-risk individuals in inpatient and population-based samples. Clinicians should pay particular attention to cardiovascular risk factors among suicide attempters in order to reduce their risk for cardiovascular events.

Electrospun Membranes Designed for Burst Release of New Gold-Complexes Inducing Apoptosis of Melanoma Cells.

Two non-commercial metallic Au-based complexes were tested against one of the most aggressive malignant melanomas of the skin (MeWo cells), through cell viability and time-lapse live-cell imaging system assays. The tests with the complexes were carried out both in the form of free metallic complexes, directly in contact with the MeWo cell line culture, and embedded in fibers of Polycaprolactone (PCL) membranes produced by the electrospinning technique. Membranes functionalized with complexes were prepared to evaluate the efficiency of the membranes against the melanoma cells and therefore their feasibility in the application as an antitumoral patch for topical use. Both series of tests highlighted a very effective antitumoral activity, manifesting a very relevant cell viability inhibition after both 24 h and 48 h. In the case of the AuM1 complex at the concentration of 20 mM, melanoma cells completely died in this short period of time. A mortality of around 70% was detected from the tests performed using the membranes functionalized with AuM1 complex at a very low concentration (3 wt.%), even after 24 h of the contact period. The synthesized complexes also manifest high selectivity with respect to the MeWo cells. The peculiar structural and morphological organization of the nanofibers constituting the membranes allows for a very effective antitumoral activity in the first 3 h of treatment. Experimental points of the release profiles were perfectly fitted with theoretical curves, which easily allow interpretation of the kinetic phenomena occurring in the release of the synthesized complexes in the chosen medium.

Prospective evaluation of the DSM-5 persistent complex bereavement disorder criteria in adults: dimensional and diagnostic approaches.

BACKGROUND: We examine the performance of the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) persistent complex bereavement-related disorder (PCBD) criteria in bereaved adults to identify prolonged grief cases determined prospectively. METHODS: Bereaved adults (n = 138) were assessed at 8, 21, 32, 67, and 90 months after the sudden death of a spouse or close relative. We used latent class growth analysis to identify the longitudinal trajectories of grief assessed using the Inventory for Complicated Grief. To validate the trajectory that corresponded to prolonged grief, we examined the baseline predictors of these trajectories and their relationship with functional impairment. RESULTS: We found three distinct trajectories of grief reactions. One of these trajectories (13.8%) showed high and sustained grief reactions that persisted for almost 7.5 years after the death. Participants with prolonged grief showed greater functional impairment [relative risk ratio (RRR) = 0.82, 95% confidence interval (CI): 0.70 to -0.97; p = 0.02] and higher self-reported depression (RRR = 1.21, 95% CI 1.09 to 1.96; p = 0.001) than participants whose grief reactions subsided over time. The original PCBD (requiring 6 criterion C symptoms) criteria correctly identified cases (57.9-94.7%) with perfect specificity (100%) but low to high sensitivity (5.6-81.3%); however, its sensitivity increased when revising criterion C to require ⩾3 (45.5-94.1%). The dimensional approach showed high sensitivity (0.50-1) and specificity (0.787-0.97). CONCLUSIONS: We recommend revisions to the PCBD criteria, which are overly restrictive and may exclude cases with clinically significant grief-related distress and impairment. In the meantime, clinicians need to monitor grief symptoms over time using available dimensional approaches to reduce the burden of grief.

Stem Cell and Macrophage Roles in Skeletal Muscle Regenerative Medicine.

In severe muscle injury, skeletal muscle tissue structure and functionality can be repaired through the involvement of several cell types, such as muscle stem cells, and innate immune responses. However, the exact mechanisms behind muscle tissue regeneration, homeostasis, and plasticity are still under investigation, and the discovery of pathways and cell types involved in muscle repair can open the way for novel therapeutic approaches, such as cell-based therapies involving stem cells and peripheral blood mononucleate cells. Indeed, peripheral cell infusions are a new therapy for muscle healing, likely because autologous peripheral blood infusion at the site of injury might enhance innate immune responses, especially those driven by macrophages. In this review, we summarize current knowledge on functions of stem cells and macrophages in skeletal muscle repairs and their roles as components of a promising cell-based therapies for muscle repair and regeneration.

Therapeutic potential of microRNA in tendon injuries.

INTRODUCTION: The regulatory role of microRNA (miRNA) in several conditions has been studied, but their function in tendon healing remains elusive. This review summarizes how miRNAs are related to the pathogenesis of tendon injuries and highlights their clinical potential, focusing on the issues related to their delivery for clinical purposes. SOURCES OF DATA: We searched multiple databases to perform a systematic review on miRNA in relation to tendon injuries. We included in the present work a total of 15 articles. AREAS OF AGREEMENT: The mechanism of repair of tendon injuries is probably mediated by resident tenocytes. These maintain a fine equilibrium between anabolic and catabolic events of the extracellular matrix. Specific miRNAs regulate cytokine expression and orchestrate proliferation and differentiation of stromal cell lines involved in the composition of the extracellular matrix. AREAS OF CONTROVERSY: The lack of effective delivery systems poses serious obstacles to the clinical translation of these basic science findings. GROWING POINT: In vivo studies should be planned to better explore the relationship between miRNA and tendon injuries and evaluate the most suitable delivery system for these molecules. AREAS TIMELY FOR DEVELOPING RESEARCH: Investigations ex vivo suggest therapeutic opportunities of miRNA for the management of tendon injuries. Given the poor pharmacokinetic properties of miRNAs, these must be delivered by an adequate adjuvant transport system.

Dose-Response Tendon-Specific Markers Induction by Growth Differentiation Factor-5 in Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells.

Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton's Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 (hGDF-5) we supplemented each at doses of 1, 10, and 100 ng/mL of hGDF-5 and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated the expression of collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis-A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed up-regulation of SCX-A (1.7-fold) at Day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX-A (3.8-fold) and TNC (2.3-fold) after three days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular-shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this, we explored the expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1ß) and anti-inflammatory (IL-10, TGF-ß1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines up-regulating IL-1ß (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold), but a greater up-regulation of IL-10 (2.5-fold). Type 1 collagen and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification with a length/width ratio increase, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue-engineering protocols.

In Vitro Innovation of Tendon Tissue Engineering Strategies.

Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process.

Liposomes for Intra-Articular Analgesic Drug Delivery in Orthopedics: State-of-Art and Future Perspectives. Insights from a Systematic Mini-Review of the Literature.

Background and objectives: Liposomal structures are artificial vesicles composed of one or several lamellae of phospholipids which surround an inner aqueous core. Given the amphoteric nature of phospholipids, liposomes are promising systems for drug delivery. The present review provides an updated synthesis of the main techniques for the production of liposomes for orthopedic applications, focusing on the drawbacks of the conventional methods and on the advantages of high pressure techniques. Materials and Methods: Articles published in any language were systematically retrieved from two major electronic scholarly databases (PubMed/MEDLINE and Scopus) up to March 2020. Nine articles were retained based on the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guidelines. Results: Liposome vesicles decrease the rate of inflammatory reactions after local injections, and significantly enhance the clinical effectiveness of anti-inflammatory agents providing controlled drug release, reducing toxic side effects. Conclusions: This review presents an update on the improvement in musculoskeletal ailments using liposome treatment.

MicroRNA in osteoarthritis: physiopathology, diagnosis and therapeutic challenge.

BACKGROUND: Osteoarthritis (OA) is the most orthopedic condition. The pattern of gene expression and the transcription factors that exert control of chondrogenesis have been extensively studied. SOURCES OF DATA: A systematic search (up to July 2018) of articles assessing the role of microRNA (miRNA) in physiopathology, diagnosis and therapy of OA was performed, with the purpose of giving a critical perspective of the possibilities for diagnostic and therapeutic use of miRNA in the management of OA. AREAS OF AGREEMENT: miRNAs are small noncoding RNAs that can regulate gene expression in human cells. miRNAs can be expressed in a different fashion in osteoarthritic compared to nonosteoarthritic cartilage. AREAS OF CONTROVERSY: The mechanisms that produce alteration of gene expression in OA are still not completely understood. miRNAs may be involved in the diagnosis of OA as well as in its treatment. GROWING POINTS: There are complex interactions between miRNAs and their multiple target genes. These interactions may be important in gene regulation and the control of homeostatic pathways in OA. AREAS TIMELY FOR DEVELOPING RESEARCH: miRNA could be useful for diagnostic or management purposes, but the issue of delivery of miRNA targeting agents needs to be overcome before miRNA can be applied in clinical practice.

Biomechanical issues of tissue-engineered constructs for articular cartilage regeneration: in vitro and in vivo approaches.

BACKGROUND: Given the limited regenerative capacity of injured articular cartilage, the absence of suitable therapeutic options has encouraged tissue-engineering approaches for its regeneration or replacement. SOURCES OF DATA: Published articles in any language identified in PubMed and Scopus electronic databases up to August 2019 about the in vitro and in vivo properties of cartilage engineered constructs. A total of 64 articles were included following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. AREAS OF AGREEMENT: Regenerated cartilage lacks the biomechanical and biological properties of native articular cartilage. AREAS OF CONTROVERSY: There are many different approaches about the development of the architecture and the composition of the scaffolds. GROWING POINTS: Novel tissue engineering strategies focus on the development of cartilaginous biomimetic materials able to repair cartilage lesions in association to cell, trophic factors and gene therapies. AREAS TIMELY FOR DEVELOPING RESEARCH: A multi-layer design and a zonal organization of the constructs may lead to achieve cartilage regeneration.

Growth factor sustained delivery from poly-lactic-co-glycolic acid microcarriers and its mass transfer modeling by finite element in a dynamic and static three-dimensional environment bioengineered with stem cells.

Poly-lactic-co-glycolic acid (PLGA) microcarriers (0.8 ± 0.2 µm) have been fabricated with a load of 20 µg/gPLGA by an emulsion-based-proprietary technology to sustained deliver human bone morphogenetic protein 2 (hBMP2), a growth factor largely used for osteogenic induction. hBMP2 release profile, measured in vitro, showed a moderate "burst" release of 20% of the load in first 3 days, followed by a sustained release of 3% of the load along the following 21 days. PLGA microbeads loaded with fluorescent marker (8 mg/gPLGA ) and hydroxyapatite (30 mg/gPLGA ) were also fabricated and successfully dispersed within three-dimensional (3D) alginate scaffold (Ca-alginate 2% wt/wt) in a range between 50 and 200 mg/cm3 ; the presence of microcarriers within the scaffold induced a variation of its stiffness between 0.03 and 0.06 MPa; whereas the scaffold surface area was monitored always in the range of 190-200 m2 /g. Uniform microcarriers dispersion was obtained up to 200 mg/cm3 ; higher loading values in the 3D scaffold produced large aggregates. The release data and the surface area were, then, used to simulate by finite element modeling the hBMP2 mass transfer within the 3D hydrogel bioengineered with stem cells, in dynamic and static cultivations. The simulation was developed with COMSOL Multiphysics® giving a good representation of hBMP2 mass balances along microbeads (bulk eroded) and on cell surface (cell binding). hBMP2 degradation rate was also taken into account in the simulations. hBMP2 concentration of 20 ng/cm3 was set as a target because it has been described as the minimum effective value for stem cells stimulation versus the osteogenic phenotype. The sensitivity analysis suggested the best microbeads/cells ratio in the 3D microenvironment, along 21 days of cultivations in both static and dynamic cultivation (perfusion) conditions. The simulated formulation was so assembled experimentally using human mesenchymal stem cells and an improved scaffold stiffness up to 0.09 MPa (n = 3; p ≤ 0.01) was monitored after 21 days of cultivation; moreover a uniform extracellular matrix deposition within the 3D system was detected by Von Kossa staining, especially in dynamic conditions. The results indicated that the described tool can be useful for the design of 3D bioengineered microarchitecture by quantitative understanding.

Childhood maltreatment, neuropsychological function and suicidal behavior.

BACKGROUND: Suicide is the second leading cause of death in young people. Childhood maltreatment, neuropsychological dysfunction and psychopathology have each been shown to increase risk for suicidal behavior. However, few studies have examined their interactions and the effects of those interactions on suicidal behavior. METHODS: Across two sites, a total of 382 offspring of depressed parents underwent neuropsychological assessments. This high-risk sample included nearly equal numbers of males and females. Average age at the time of neuropsychological assessment was 18.5 years. The most prevalent lifetime psychiatric disorders were mood (43%), anxiety (37%) and alcohol and substance use disorders (21%). Childhood maltreatment was reported by 44% of offspring. Participants underwent extensive neuropsychological testing assessing the following domains: attention, memory, executive function, working memory, language fluency, and impulse control. Logistic regression was used to examine the association of reported childhood maltreatment, neuropsychological functioning, psychopathology and their interactions with suicidal behavior. Bonferroni correction was used to adjust for multiple comparisons. RESULTS: Maltreatment was associated with increased risk of suicidal behavior with odds ratios ranging between 2.40 and 4.43. Moderation analyses found that adaptive neuropsychological functioning was not protective against childhood maltreatment's effect on suicidal risk. While lifetime history of mood disorder was strongly associated with suicidal behavior, higher scores in working memory (OR = 0.21; 95% CI = 0.09, 0.45; p < .001) and executive function (OR = 0.15; 95% CI = 0.05, 0.43; p < .001) were protective against suicidal behavior even in the presence of a lifetime history of mood disorder. CONCLUSIONS: Further research is needed to determine how neuropsychological capacity protects depressed patients against the risk of suicidal behavior.