Skin Tolerability of Oleic Acid Based Nanovesicles Designed for the Improvement of Icariin and Naproxen Percutaneous Permeation.

Deformable nanovesicles have a crucial role in topical drug delivery through the skin, due to their capability to pass intact the stratum corneum and epidermis (SCE) and significantly increase the efficacy and accumulation of payloads in the deeper layers of the skin. Namely, lipid-based ultradeformable nanovesicles are versatile and load bioactive molecules with different physicochemical properties. For this reason, this study aims to make oleic acid based nanovesicles (oleosomes) for the codelivery of icariin and sodium naproxen and increase their permeation through the skin. Oleosomes have suitable physicochemical properties and long-term stability for a potential dermal or transdermal application. The inclusion of oleic acid in the lipid bilayer increases 3-fold the deformable properties of oleosomes compared to conventional liposomes and significantly improves the percutaneous permeation of icariin and sodium naproxen through the human SCE membranes compared to hydroalcoholic solutions of both drugs. The tolerability studies on human volunteers demonstrate that oleosomes are safer and speed up the recovery of transepidermal water loss (TEWL) baselines compared to saline solution. These results highlight promising properties of icariin/sodium naproxen coloaded oleosomes for the treatment of skin disorders and suggest the potential future applications of these nanovesicles for further in vivo experiments.

OX26-cojugated gangliosilated liposomes to improve the post-ischemic therapeutic effect of CDP-choline.

Cerebrovascular impairment represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. The disability of 50% of surviving patients has high social impacts and costs in long period treatment for national healthcare systems. For these reasons, the efficacious clinical treatment of patients, with brain ischemic stroke, remains a medical need. To this aim, a liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) was prepared. CDP-choline/OX26Lip were prepared by a freeze and thaw method and then extruded through polycarbonate filters, to have narrow size distributed liposomes of ~80 nm. CDP-choline/OX26Lip were stable in human serum, they had suitable pharmacokinetic properties, and 30.0 ± 4.2% of the injected drug was still present in the blood stream 12 h after its systemic injection. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is higher than CDP-choline/Lip, thus showing a significantly high survival rate of the re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of ~5-times compared to CDP-choline/Lip; and the resulting conjugated dienes, that was 13.9 ± 1.1 mmol/mg proteins for CDP-choline/Lip and 3.1 ± 0.8 for CDP-choline/OX26Lip. OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline. Therefore, this nanomedicine may represent a strategy for the reassessment of CDP-choline to treat post-ischemic events caused by brain stroke, and respond to a significant clinical need.

Thermoresponsive M1 macrophage-derived hybrid nanovesicles for improved in vivo tumor targeting.

Despite the efforts and advances done in the last few decades, cancer still remains one of the main leading causes of death worldwide. Nanomedicine and in particular extracellular vesicles are one of the most potent tools to improve the effectiveness of anticancer therapies. In these attempts, the aim of this work is to realize a hybrid nanosystem through the fusion between the M1 macrophages-derived extracellular vesicles (EVs-M1) and thermoresponsive liposomes, in order to obtain a drug delivery system able to exploit the intrinsic tumor targeting capability of immune cells reflected on EVs and thermoresponsiveness of synthetic nanovesicles. The obtained nanocarrier has been physicochemically characterized, and the hybridization process has been validated by cytofluorimetric analysis, while the thermoresponsiveness was in vitro confirmed through the use of a fluorescent probe. Tumor targeting features of hybrid nanovesicles were in vivo investigated on melanoma-induced mice model monitoring the accumulation in tumor site through live imaging and confirmed by cytofluorimetric analysis, showing higher targeting properties of hybrid nanosystem compared to both liposomes and native EVs. These promising results confirmed the ability of this nanosystem to combine the advantages of both nanotechnologies, also highlighting their potential use as effective and safe personalized anticancer nanomedicine.

Surface display of functional moieties on extracellular vesicles using lipid anchors.

Extracellular vesicles (EVs) are efficient natural vehicles for intercellular communication and are under extensive investigation for the delivery of diverse therapeutics including small molecule drugs, nucleic acids, and proteins. To understand the mechanisms behind the biological activities of EVs and develop EV therapeutics, it's fundamental to track EVs and engineer EVs in a customized manner. In this study, we identified, using single-vesicle flow cytometry and microscopy, the lipid DOPE (dioleoyl phosphatidyl ethanolamine) as an efficient anchor for isolated EVs. Notably, DOPE associated with EVs quickly, and the products remained stable under several challenging conditions. Moreover, conjugating fluorophores, receptor-targeting peptides or albumin-binding molecules with DOPE enabled tracking the cellular uptake, enhanceing the cellular uptake or extending the circulation time in mice of engineered EVs , respectively. Taken together, this study reports an efficient lipid anchor for exogenous engineering of EVs and further showcases its versatility for the functionalization of EVs.

Oleic acid-based vesicular nanocarriers for topical delivery of the natural drug thymoquinone: Improvement of anti-inflammatory activity.

The topical administration of a drug compound remains the first choice for the treatment of many local skin ailments. Many skin diseases can be treated by applying the active formulation directly to the skin, but unfortunately some drugs are unable to overcome the stratum corneum and exert their pharmacological action. An example is thymoquinone, a naturally derived drug obtained from Nigella sativa L. and potentially effective in the treatment of inflammatory and oxidative skin conditions. Since its physico-chemical properties are not suitable for overcoming the stratum corneum, we wanted to circumvent the problem by proposing new lipid-based nanovesicles called "oleoethosomes", made up of naturally derived ingredients, for its delivery. Among several formulations of oleoethosomes, the sample made up of 2% (w/w) oleic acid:PL90G 1:1 (molar ratio), and ethanol 15% showed the best physico-chemical characteristics and above all it showed the capacity to contain a suitable amount of thymoquinone (2 mg/ml). The formulation was tested in vitro on stratum corneum and viable epidermis membranes confirming its ability to induce the passage of thymoquinone through the human stratum corneum and to act as a permeation enhancer. In fact, it showed thymoquinone permeation values of 22.63 ± 1.49% regarding the applied drug amount. Oleoethosomes were compared with oleosomes, another kind of naturally derived nanosystems but free of ethanol. The experimental data confirmed that ethanol was an important component that enhanced the activity of the oleoethosomes when tested on the skin of healthy volunteers. The thymoquinone-loaded oleoethosome treatment demonstrated a significantly greater extent of anti-inflammatory activity than the treatment with thymoquinone-loaded oleosomes or the conventional dosage form of the drug. These in vivo results confirmed the synergic effect between oleic acid and ethanol on the lipid and protein compartments of the outermost skin layer, thus promoting a greater penetration capacity.

Association between multidimensional prognostic index (MPI) and pre-operative delirium in older patients with hip fracture.

Pre-operative delirium may cause delay in surgical intervention in older patients hospitalized for hip fracture. Also it has been associated with higher risk of post-surgical complications and worst functional outcomes. Aim of this retrospective cohort study was to evaluate whether the multidimensional prognostic index (MPI) at hospital admission was associated with pre-operative delirium in older individuals with hip fracture who are deemed to require surgical intervention. Consecutive older patients (≥ 65 years) with hip fracture underwent a comprehensive geriatric assessment to calculate the MPI at hospital admission. According to previously established cut-offs, MPI was expressed in three grades, i.e. MPI-1 (low-risk), MPI-2 (moderate-risk) and MPI-3 (high risk of mortality). Pre-operative delirium was assessed using the four 'A's Test. Out of 244 older patients who underwent surgery for hip fracture, 104 subjects (43%) received a diagnosis of delirium. Overall, the incidence of delirium before surgery was significantly higher in patients with more severe MPI score at admission. Higher MPI grade (MPI-3) was independently associated with higher risk of pre-operative delirium (OR 2.45, CI 1.21-4.96). Therefore, the MPI at hospital admission might help in early identification of older patients with hip fracture at risk for pre-operative delirium.

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy.

The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies' efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor's progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell-cell and organ-cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer's fate as well as their potential implications for the development of personalized anticancer nanomedicine.

Ammonium Glycyrrhizinate and Bergamot Essential Oil Co-Loaded Ultradeformable Nanocarriers: An Effective Natural Nanomedicine for In Vivo Anti-Inflammatory Topical Therapies.

Bergamot essential oil (BEO) and Ammonium glycyrrhizinate (AG), naturally derived compounds, have remarkable anti-inflammatory properties, thus making them suitable candidates for the treatment of skin disorders. Despite this, their inadequate physicochemical properties strongly compromise their topical application. Ultradeformable nanocarriers containing both BEO and AG were used to allow their passage through the skin, thus maximizing their therapeutic activity. Physicochemical characterization studies were performed using Zetasizer Nano ZS and Turbiscan Lab®. The dialysis method was used to investigate the release profile of the active compounds. In vivo studies were performed on human healthy volunteers through the X-Rite spectrophotometer. The nanosystems showed suitable features for topical cutaneous administration in terms of mean size, surface charge, size distribution, and long-term stability/storability. The co-delivery of BEO and AG in the deformable systems improved both the release profile kinetic of ammonium glycyrrhizinate and deformability properties of the resulting nanosystems. The topical cutaneous administration on human volunteers confirmed the efficacy of the nanosystems. In detail, BEO and AG-co-loaded ultradeformable vesicles showed a superior activity compared to that recorded from the ones containing AG as a single agent. These results are promising and strongly encourage a potential topical application of AG/BEO co-loaded nanocarriers for anti-inflammatory therapies.

Rutin-Loaded Nanovesicles for Improved Stability and Enhanced Topical Efficacy of Natural Compound.

Rutin is a natural compound with several pharmacological effects. Among these, antioxidant activity is one of the best known. Despite its numerous benefits, its topical application is severely limited by its physicochemical properties. For this reason, the use of suitable systems could be necessary to improve its delivery through skin, thus enhancing its pharmacological effects. In this regard, the aim of this work is to optimize the ethosomal dispersion modifying both lipid and ethanol concentrations and encapsulating different amounts of rutin. Characterization studies performed on the realized systems highlighted their great stability properties. Studies of encapsulation efficiency and loading degree allowed us to identify a better formulation (EE% 67.5 ± 5.2%, DL% 27 ± 1.7%), which was used for further analyses. The data recorded from in vitro studies showed that the encapsulation into these nanosystems allowed us to overcome the photosensitivity limitation of rutin. Indeed, a markable photostability of the loaded formulation was recorded, compared with that reported from the free rutin solution. The efficacy of the nanosystems was finally evaluated both in vitro on keratinocyte cells and in vivo on human healthy volunteers. The results confirmed the potentiality of rutin-loaded nanosystems for skin disease, mainly related to their anti-inflammatory and antioxidant effects.

Multidimensional prognostic index and the risk of fractures: an 8-year longitudinal cohort study in the Osteoarthritis Initiative.

In this longitudinal study, with a follow-up of 8 years, multidimensional prognostic index (MPI), a product of the comprehensive geriatric assessment, significantly predicted the onset of fractures in older people affected by knee osteoarthritis. PURPOSE: Frailty may be associated with higher fracture risk, but limited research has been carried out using a multidimensional approach to frailty assessment and diagnosis. The present research aimed to investigate whether the MPI, based on comprehensive geriatric assessment (CGA), is associated with the risk of fractures in the Osteoarthritis Initiative (OAI) study. METHODS: Community-dwellers affected by knee OA or at high risk for this condition were followed-up for 8 years. A standardized CGA including information on functional, nutritional, mood, comorbidity, medication, quality of life, and co-habitation status was used to calculate the MPI. Fractures were diagnosed using self-reported information. Cox's regression analysis was carried out and results are reported as hazard ratios (HRs), with their 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: The sample consisted of 4024 individuals (mean age 61.0 years, females = 59.0%). People with incident fractures had a significant higher MPI baseline value than those without (0.42 ± 0.18 vs. 0.40 ± 0.17). After adjusting for several potential confounders, people with an MPI over 0.66 (HR = 1.49; 95%CI: 1.11-2.00) experienced a higher risk of fractures. An increase in 0.10 point in MPI score corresponded to an increase in fracture risk of 4% (HR = 1.04; 95%CI: 1.008-1.07). Higher MPI values were also associated with a higher risk of non-vertebral clinical fractures. CONCLUSION: Higher MPI values at baseline were associated with an increased risk of fractures, reinforcing the importance of CGA in predicting fractures in older people affected by knee OA.

In vitro CSC-derived cardiomyocytes exhibit the typical microRNA-mRNA blueprint of endogenous cardiomyocytes.

miRNAs modulate cardiomyocyte specification by targeting mRNAs of cell cycle regulators and acting in cardiac muscle lineage gene regulatory loops. It is unknown if or to-what-extent these miRNA/mRNA networks are operative during cardiomyocyte differentiation of adult cardiac stem/progenitor cells (CSCs). Clonally-derived mouse CSCs differentiated into contracting cardiomyocytes in vitro (iCMs). Comparison of "CSCs vs. iCMs" mRNome and microRNome showed a balanced up-regulation of CM-related mRNAs together with a down-regulation of cell cycle and DNA replication mRNAs. The down-regulation of cell cycle genes and the up-regulation of the mature myofilament genes in iCMs reached intermediate levels between those of fetal and neonatal cardiomyocytes. Cardiomyo-miRs were up-regulated in iCMs. The specific networks of miRNA/mRNAs operative in iCMs closely resembled those of adult CMs (aCMs). miR-1 and miR-499 enhanced myogenic commitment toward terminal differentiation of iCMs. In conclusions, CSC specification/differentiation into contracting iCMs follows known cardiomyo-MiR-dependent developmental cardiomyocyte differentiation trajectories and iCMs transcriptome/miRNome resembles that of CMs.

A novel effervescent formulation of oral weekly alendronate (70 mg) improves persistence compared to alendronate tablets in post-menopausal women with osteoporosis.

BACKGROUND: A novel effervescent buffered solution of 70 mg alendronate (ALN-EX) was developed to improve upper gastrointestinal (GI) tolerability over alendronate tablets (ALN-T). Whether a better GI tolerability can improve persistence remains to be determined. AIM: This study evaluated persistence and reasons for discontinuation in patients treated with ALN-EX compared to a historical cohort on ALN-T. METHODS: Post-menopausal women (PMW) from a standardized clinical database with BMD T-score < -2.5, or between -2 and -2.5 and at least one vertebral fracture, starting ALN-EX between July 2015 and June 2016 were included. A historical cohort comprised of randomly selected and age-matched PMW on ALN-T was used as a control. Persistence at 6 and 12 months and reasons for discontinuation (e.g. adverse events; AE) were compared between the two groups. RESULTS: A total of 144 PMW on ALN-EX and 216 PMW on ALN-T were analysed. Persistence at 6 and 12 months was 91% and 81% in the ALN-EX group vs. 75% and 69% in the ALN-T group, this difference attaining statistical significance at both 6- (p < 0.001) and 12 months (p = 0.009). A significantly higher proportion of patients receiving ALN-T discontinued treatment due to GI AEs (4% ALN-EX vs. 11% ALN-T; p = 0.027), or patient's decision to discontinue (6% ALN-EX vs. 13% ALN-T; p = 0.016). The adjusted odds ratio of persisting on ALN-EX treatment at 12 months was 2.02 (95% CI: 1.21-3.41, p = 0.008). CONCLUSION: Our findings demonstrate that ALN-EX can provide greater persistence and improved tolerability compared to ALN-T, allowing it to be a viable alternative option in the management of osteoporosis.

Cardiac Stem Cell-Loaded Delivery Systems: A New Challenge for Myocardial Tissue Regeneration.

Cardiovascular disease (CVD) remains the leading cause of death in Western countries. Post-myocardial infarction heart failure can be considered a degenerative disease where myocyte loss outweighs any regenerative potential. In this scenario, regenerative biology and tissue engineering can provide effective solutions to repair the infarcted failing heart. The main strategies involve the use of stem and progenitor cells to regenerate/repair lost and dysfunctional tissue, administrated as a suspension or encapsulated in specific delivery systems. Several studies demonstrated that effectiveness of direct injection of cardiac stem cells (CSCs) is limited in humans by the hostile cardiac microenvironment and poor cell engraftment; therefore, the use of injectable hydrogel or pre-formed patches have been strongly advocated to obtain a better integration between delivered stem cells and host myocardial tissue. Several approaches were used to refine these types of constructs, trying to obtain an optimized functional scaffold. Despite the promising features of these stem cells' delivery systems, few have reached the clinical practice. In this review, we summarize the advantages, and the novelty but also the current limitations of engineered patches and injectable hydrogels for tissue regenerative purposes, offering a perspective of how we believe tissue engineering should evolve to obtain the optimal delivery system applicable to the everyday clinical scenario.

Ammonium glycyrrhizate skin delivery from ultradeformable liposomes: A novel use as an anti-inflammatory agent in topical drug delivery.

Glycyrrhiza glabra L. is a native plant of Central and South-Western Asia that is also diffused in the Mediterranean area and contains several bioactive compounds such as: flavonoids, sterols, triterpene and saponins. Glycyrrhizin, containing glycyrrhizic and glycyrrhizinic acids has anti-inflammatory and antiallergic effects that are similar to corticosteroids. Ammonium glycyrrhizinate is a derivative salt of glycyrrhizic acid with similar anti-inflammatory activity that cannot pass through the skin due to its physicochemical properties and molecular weight. Although several nanoformulations, such as ethosomes, are designed to provide a systemic effect through a topical application, there are different limitations to the distribution inside the blood stream. For this reason, ultradeformable liposomes, or transfersomes, are selected to improve the topical delivery of drugs and allow the distribution of payloads in the blood stream because they pass intact through the stratum corneum epidermis barrier, due to the presence of sodium cholate, aqueous cutaneous gradient, and the rapid penetration of transfersomes by cutaneous tight junctions, thus allowing the systemic delivery of different therapeutic cargo in non-occlusive conditions. The aim of this work was the synthesis and physicochemical characterization of the ammonium glycyrrhizinate-loaded ultradeformable liposomes, the evaluation of drug release and permeation through stratum corneum and epidermis barrier. The in vivo anti-inflammatory effect of ammonium glycyrrhizinate-loaded ultradeformable liposomes was tested on human healthy volunteers. The results demonstrated that the ammonium glycyrrhizinate-loaded ultradeformable liposomes decreased the skin inflammation on the human volunteers and the resulting nanoformulations can be used as a potential topical drug delivery system for anti-inflammatory therapy. ☆Parts of these results were presented as a poster communication at the Recent Developments in Pharmaceutical Analysis 2019 (RDPA 2019), Chieti, Italy.

Unravelling the Biology of Adult Cardiac Stem Cell-Derived Exosomes to Foster Endogenous Cardiac Regeneration and Repair.

Cardiac remuscularization has been the stated goal of the field of regenerative cardiology since its inception. Along with the refreshment of lost and dysfunctional cardiac muscle cells, the field of cell therapy has expanded in scope encompassing also the potential of the injected cells as cardioprotective and cardio-reparative agents for cardiovascular diseases. The latter has been the result of the findings that cell therapies so far tested in clinical trials exert their beneficial effects through paracrine mechanisms acting on the endogenous myocardial reparative/regenerative potential. The endogenous regenerative potential of the adult heart is still highly debated. While it has been widely accepted that adult cardiomyocytes (CMs) are renewed throughout life either in response to wear and tear and after injury, the rate and origin of this phenomenon are yet to be clarified. The adult heart harbors resident cardiac/stem progenitor cells (CSCs/CPCs), whose discovery and characterization were initially sufficient to explain CM renewal in response to physiological and pathological stresses, when also considering that adult CMs are terminally differentiated cells. The role of CSCs in CM formation in the adult heart has been however questioned by some recent genetic fate map studies, which have been proved to have serious limitations. Nevertheless, uncontested evidence shows that clonal CSCs are effective transplantable regenerative agents either for their direct myogenic differentiation and for their paracrine effects in the allogeneic setting. In particular, the paracrine potential of CSCs has been the focus of the recent investigation, whereby CSC-derived exosomes appear to harbor relevant regenerative and reparative signals underlying the beneficial effects of CSC transplantation. This review focuses on recent advances in our knowledge about the biological role of exosomes in heart tissue homeostasis and repair with the idea to use them as tools for new therapeutic biotechnologies for "cell-less" effective cardiac regeneration approaches.

Three-year National report from the Gruppo Italiano di Ortogeriatria (GIOG) in the management of hip-fractured patients.

BACKGROUND: Hip fractures (HF) are a major issue worldwide. We aimed at evaluating the practices in delivering care to patients with HF among several Italian Orthogeriatric centers. METHODS: The study took place from February 2016 to July 2018. Seven performance indicators (pre-surgical cognitive assessment, surgery performed ≤ 48 h from fracture, removal of urinary catheter/absence of delirium/start of physiotherapy on the first post-operative day, prescription of bone protection at discharge, and discharge toward rehabilitation) were collected. RESULTS: The 14 participating hospitals totally recruited 3.017 patients. Patients were old (median age 86 years; Inter Quartile Range [IQR] 80-90), mostly females (77%). Nearly 55% of them were already impaired in mobility and about 10% were nursing home residents. Median time-to-surgery was 41 h (IQR 23-62). Models of care greatly varied among centers, only 49.3% of patients being co-managed by geriatricians and orthopedics. There was high variability across centers in four indicators ("pre-surgical cognitive assessment", "bone protection prescription", "use of urinary catheter" and "start of physiotherapy"), moderate in two indicators ("surgery performed ≤ 48 h from fracture" and "discharge toward rehabilitation" and low in one ("absence of delirium on day following surgery"). Comparison with international studies suggests very different ways of providing care to HF Italian patients. CONCLUSIONS: The study results suggest high inter-center variability in the key-performance indicators, and different approaches in providing care to our HF patients in comparison to other countries. A National debate on the topic is required in Italy to harmonize practices of orthogeriatric care.

The Multidimensional Prognostic Index Predicts Falls in Older People: An 8-Year Longitudinal Cohort Study of the Osteoarthritis Initiative.

OBJECTIVES: Falls are associated with several negative outcomes. Early identification of those who are at risk of falling is of importance in geriatrics, and comprehensive geriatric assessment (CGA) seems to be promising in this regard. Therefore, the present study investigated whether the multidimensional prognostic index (MPI), based on a standard CGA, is associated with falls in the Osteoarthritis Initiative (OAI). DESIGN: Longitudinal, 8 years of follow-up. SETTING AND PARTICIPANTS: Community-dwelling older people (≥65 years of age) with knee osteoarthritis or at high risk for this condition. METHODS: A standardized CGA including information on functional, nutritional, mood, comorbidities, medications, quality of life, and cohabitation status was used to calculate a modified version of the MPI, categorized as MPI-1 (low), MPI-2 (moderate), and MPI-3 (high risk). Falls were self-reported and recurrent fallers were defined as ≥2 in the previous year. Logistic regression was carried out and results are reported as odds ratio (ORs) with their 95% confidence intervals (CIs). RESULTS: The final sample consisted of 885 older adults (mean age 71.3 years, female = 54.6%). Recurrent fallers showed a significant higher MPI than their counterparts (0.46 ± 0.17 vs 0.38 ± 0.16; P < .001). Compared with those in MPI-1 category, participants in MPI-2 (OR 2.13; 95% CI 1.53‒2.94; P < .001) and in MPI-3 (OR 5.98; 95% CI 3.29-10.86; P < .001) reported a significant higher risk of recurrent falls over the 8-years of follow-up. Similar results were evident when using an increase in 0.1 points in the MPI or risk of falls after 1 year. CONCLUSIONS AND IMPLICATIONS: Higher MPI values at baseline were associated with an increased risk of recurrent falls, suggesting the importance of CGA in predicting falls in older people.

Hybrid Nanostructured Films for Topical Administration of Simvastatin as Coadjuvant Treatment of Melanoma.

This work aims at (1) assessing the potential of repurposing simvastatin (SV) to support the most common therapies against melanoma and (2) developing an innovative topical adhesive film, composed by chitosan-coated nanostructured lipid carriers (Ch-NLC) used as drug vehicle. A factorial design approach was employed as the basis for the formulation development. Optimized Ch-NLC displayed a particle size of 108 ± 1 nm, a polydispersity index of 0.226, a zeta potential of 17.0 ± 0.6 mV, as well as an entrapment efficiency of 99.86 ± 0.08%, and SV loading of 14.99 ± 0.01%. The performance of SV-Ch-NLC films was assessed in terms of release, permeation, and adhesion, as critical quality attributes. Cutaneous tolerability and in vitro cytotoxicity studies were performed to warrant film safety and drug effectiveness, respectively. The topical films provided a sustained release kinetic profile of SV and were classified as nonirritant systems. The encapsulation of SV increased cytotoxicity in melanoma cells. The key role of squalene as nanostructuring agent of the lipid nanoparticle matrix and as permeation enhancer was highlighted, suggesting its key action for potentiating skin permeation and uptake into melanoma cells. Topical SV-Ch-NLC films are thus able to provide an in situ extended drug delivery and useful as coadjuvant treatment of melanoma skin lesions.

Short-term and Long-lasting Effects of Hypo-Cariogenic Dietary Advice and Oral Care on Oral Flora: a Randomised Clinical Trial.

PURPOSE: To investigate the short- and long-term effects of different combinations of dietary instructions on cariogenic food intake and salivary cariogenic bacteria (Streptococcus mutans [SM] and Lactobacillus [LB]). MATERIALS AND METHODS: In this randomised 2-arm parallel study, 75 6-year-old subjects were assigned to repeated (group A; 19M/19F) or isolated (group B; 17M/20F) verbal and/or written dietary advice (VWDA), with foods classified by cariogenic potential. Both groups underwent a baseline salivary test for SM/LB, kept a monthly food diary, and attended 4 weekly visits (T1-T4). At T1-T2; group A only received VDA. At T3, both groups received VWDA. At T4, participants handed in their food diaries and underwent another salivary test. After 1 year (T5), subjects were recalled for weekly food diary monitoring and salivary testing. Relative risk (RR) of high-to-low SM/LB density was calculated at T4 and T5. RESULTS: Comparing groups A and B, VDA determined an increase in the intake of weakly cariogenic food (p < 0.05) and a decrease in that of intermediately cariogenic food (p < 0.05). After VWDA, a statistically significant increase in intake of weakly cariogenic food and a statistically significant decrease in the RR of high-density SM/LB colonies occurred in both groups. At T5, group A showed less intake of highly cariogenic food than did group B (p = 0.05) and persistent, although non-significant, reduction in the RR of high-density SM/LB colonies. CONCLUSIONS: Reinforcement measures on behavioural changes towards a noncariogenic diet not only help maintain long-lasting, healthier eating habits, but also decrease the cariogenic bacterial load in the short term, which tends to persist over time.

Vertebral morphometry by X-ray absorptiometry: which reference data for vertebral heights?

INTRODUCTION: The recent improvement in the resolution of dual-energy X-ray absorptiometry (DXA) images enables most vertebral levels to be seen adequately and thus DXA may be a worthwhile alternative to radiologic morphometry for the identification of vertebral fractures (VF). In this multicenter study, we have derived reference data for vertebral heights and their ratios in Italian women using morphometric X-ray absorptiometry (MXA). METHODS: DXA scans were acquired in 1254 consecutive pre- and postmenopausal women, (mean age 63.7 ± 11.3, range 26-88 yrs), referred to six osteoporosis centers. MXA analysis of these images was performed by the same operator measuring vertebral heights and height ratios from L4 to T4. We calculated measures of central tendency and dispersion of vertebral heights and vertebral ratios using different approaches (mean and standard deviation as well as median and interquartile range of raw data, mean and standard deviation of trimmed data using an iterative algorithm, and mean and standard deviation of not fractured vertebrae). RESULTS: Independently of the approach that we used, all the measures of central tendency were similar, while significant differences were found when compared with reference ranges in other populations. The vertebral heights of our sample at every vertebral level were significantly smaller than both Rea population and the Lunar reference values, even after normalization. Splitting data according to age groups, there was a decrease in the vertebral heights and ratios between the younger and older women. CONCLUSIONS: This study demonstrates that reference data for MXA should be population specific and age matched.