Tumor enlargement in adrenal incidentaloma is related to glaucoma: a new prognostic feature?

PURPOSE: The uncertainty on the management of small adrenal incidentalomas (AIs) still represents a challenge in real clinical practice. Considering the lack of knowledge on risk factors implicated in tumour enlargement, the aim of this study was to identify risk factors for morphological changes during follow-up of adrenal incidentalomas (AIs). METHODS: We retrospectively evaluated demographic, clinical, radiological and biochemical parameters of 153 AIs (2007-2021). Patients with histological diagnosis of metastases or pheochromocytoma were excluded. To detect risk factors for tumor enlargement, diseases associated with AIs were included if their prevalence was higher than 2%. Patients were divided into two groups (A: radiological stability; B: tumor enlargement defined as > 5 mm/year in the main diameter). RESULTS: Group A: 89.5% and group B: 10.5%, mean follow-up 38.6 ± 6.9 months (range 6-240). Tumor enlargement when occurred was within 36 months of follow-up. In group B high body weight (p < 0.03), dehydroepiandrosterone sulfate (DHEAS) (p < 0.05) and direct renin concentration (DRC) (p < 0.04) were higher than group A, while aldosterone levels were lower; moreover, considering comorbidities, glaucoma and dysglycemia (p < 0.01 for both) had higher prevalence in group B. Glaucoma and dysglycemia were independent predictors of enlargement. Patients affected by glaucoma, atrial fibrillation, dysglycemia had a lower dimensional change-free survival than non-affected. CONCLUSIONS: Glaucoma might be a novel risk factor for AI enlargement. If subtle undetectable cortisol hypersecretion has a role is a topic for further research.

Heterogeneity in regional changes in body composition induced by androgen deprivation therapy in prostate cancer patients: potential impact on bone health-the BLADE study.

BACKGROUND: It is not clear whether changes in body composition induced by androgen deprivation therapy (ADT) in prostate cancer (PC) patients are uniform or vary in the different body districts and whether regional lean body mass (LBM) and fat body mass (FBM) could have an impact on bone health. OBJECTIVE: To prospectively evaluate the regional changes in LBM and FBM in PC patients submitted to degarelix; to explore the relationship of regional body composition and bone mineral density (BMD) and bone turnover markers. DESIGN, SETTING, AND PARTICIPANTS: 29 consecutive non metastatic PC patients enrolled from 2017 to 2019. FBM, LBM and bone mineral density (BMD) evaluated by dual-energy x-ray absorptiometry (DXA) at baseline and after 12-month of ADT. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) assessed at baseline, 6 and 12 months. INTERVENTION: All patients underwent degarelix administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: T-test or sign test and Pearson or Spearman test for continuous variables were used when indicated. RESULTS AND LIMITATIONS: Median percent increase in FBM ranged from + 14.5% in trunk to + 25.4% in the left leg after degarelix. LBM changes varied from + 2% in the trunk to - 4.9% in the right arm. LBM in both arms and legs and their variations after degarelix directly correlated with ALP and inversely correlated with CTX. Lean mass of limbs, trunk and legs significantly correlated with BMD of the hip, lean mass of the trunk significantly correlated with spine BMD. These are post-hoc analysis of a prospective study and this is the main limitation. CONCLUSIONS: an heterogeneous change in body composition among body district is observed after ADT and bone turnover is influenced by lean mass and its variation. A supervised physical activity is crucial to maintain general physical performance and preserving bone health.

The role of intralaminar damages on the delamination evolution in laminated composite structures.

Delamination is a major failure mode affecting laminated composite structures. This failure mechanism, if not properly monitored, can lead to uncontrolled cracks growth and premature structural collapse. Thus, predicting delamination propagation is mandatory to determine the structural integrity. At present, delamination has been extensively investigated in laminated composite structures but only a few studies have been performed on how the intralaminar damages influence the interfacial release energy and, consequently, the delamination evolution. In this paper, the well-established SMart-Time XB delamination simulation tool, has been coupled with a Hashin Criteria based User-Material Subroutine (UserMat) to study the role of the intralaminar damages in delamination propagation. A benchmark case based on the mixed-mode I/II Single Leg Bending (SLB) specimen for delamination evolution assessment under quasi-static loading has been investigated. Subsequently, a composite material plate, characterized by an artificial circular delamination, under compression has been considered. This study proved to be valuable by underlining the influence of fibre and matrix breakage on the interlaminar damages evolution. Interestingly, taking into account the effect of intralaminar flaws changes the local energy release rates values on the delamination front and, consequently, the crack shape and evolution.

In-vivo evaluations of bone regenerative potential of two novel bioactive glasses.

Due to the aging of population, materials able to repair damaged tissues are needed. Among others, bioactive glasses (BGs) have attracted a lot of interest due to their outstanding properties both for hard and soft tissues. Here, for the first time, two new BGs, which gave very promising results in preliminary in vitro-tests, were implanted in animals in order to evaluate their regenerative potential. The new BGs, named BGMS10 and Bio_MS and containing specific therapeutic ions, were produced in granules and implanted in rabbits' femurs for up to 60 days, to test their biocompatibility and osteoconduction. Additionally, granules of 45S5 Bioglass® were employed and used as a standard reference for comparison. The results showed that, after 30 days, the two novel BGs and 45S5 displayed a similar behavior, in terms of bone amount, thickness of new bone trabeculae and affinity index. On the contrary, after 60 days, 45S5 granules were mainly surrounded by wide and scattered bone trabeculae, separated by large amounts of soft tissue, while in BGMS10 and Bio_MS the trabeculae were thin and uniformly distributed around the BG granules. This latter scenario could be considered as more advantageous, since the features of the two novel BG granules allowed for the neo-formation of a uniformly distributed bony trabeculae, predictive of more favorable mechanical behavior, compared to the less uniform coarse trabeculae, separated by large areas of soft tissue in 45S5 granules. Thus, BGMS10 and Bio_MS could be considered suitable products for tissue regeneration in the orthopedic and dental fields.

Additive manufactured polymeric shock absorbers for automotive applications.

This paper deals with the use of shock absorbers, placed in the upper roof of vehicles, able to increase the safety of passengers during an impact event. Numerical impact analyses have been introduced to demonstrate the effectiveness of these shock absorbers by assessing the deformations, stress and energy dissipation capabilities in the different structural components of a vehicle, somehow related to the safety of passengers. Indeed, shock absorbers have been found to play an important role in relation to passengers' safety. The homologation limitations of the reference regulation have been taken into account: FMVSS No. 201U "internal head impact - passenger compartment". This regulation, actually, provides a fundamental parameter, known as HIC(d) - "Head Injury Criteria", which is strictly related to the injuries of the passenger head under impact conditions alongside the rigid components inside the vehicle. The HIC(d) threshold value, if exceeded, affects the final conformity test of a vehicle. Hence, to fall within the range of reliable values of the HIC(d), shock absorbers need to be adopted. In order to increase these shock absorbers efficiency, in terms of passenger safety, in compliance with the regulations, the possibility of production of such devices by additive manufacturing techniques has been assessed.

How painful are cats after neutering - a field study using multimodal analgesia with intraperitoneal ropivacaine in a -neuter-return program in feral cats.

INTRODUCTION: For a large-scale trap-neuter-return program 119 cats were anaesthetised with an intramuscular combination of 0,03-0,05 mg/kg medetomidine, 7-10 mg/kg ketamine and 0,4 mg/kg butorphanol. Cats received intraoperative 4 mg/kg tolfenamic acid subcutaneously and before closure of abdominal wall either 2 mg/kg ropivacaine (ROPI) intraperitoneal or saline (NaCl) in equal volumes. Pain was scored one, six and 20 hours postoperative with the modified Glasgow Composite Pain Scale (mGCPS) and the modified Colorado State University Scale (mCSU). There was no significant difference in the pain scores between the two groups, but the pain scores with both pain scales were significant higher (p < 0,001 for both) six hours compared to one and 20 hours postoperative. Cut-off value on the pain scales (necessitating rescue analgesia) was exceeded in 34,5 % for mGCPS and in 39,5 % for mCSU. Cats with a higher pain score showed a lower food intake (p .

INTRODUCTION: L'objectif de cette étude clinique prospective, randomisée, en aveugle et d'observation était d'étudier les effets de la ropivacaïne administrée par voie intrapéritonéale pour l'analgésie postopératoire chez des chats harets femelles subissant une ovariectomie. Dans le cadre d'un programme de piégeage, de stérilisation et de remise en liberté à grande échelle, 119 chattes ont été anesthésiées par une combinaison intramusculaire de 0,03 à 0,05 mg/kg de médétomidine, 7 à 10 mg/kg de kétamine et 0,4 mg/kg de butorphanol. Les chats ont reçu en peropératoire 4 mg/kg d'acide tolfénamique par voie sous-cutanée et, avant la fermeture de la paroi abdominale, 2 mg/kg de ropivacaïne (ROPI) par voie intrapéritonéale ou du sérum physiologique (NaCl) en volumes égaux. La douleur a été évaluée une, six et 20 heures après l'opération à l'aide de l'échelle de Glasgow de la douleur composite modifiée (mGCPS) et de l'échelle modifiée de l'Université d'État du Colorado (mCSU). Il n'y avait pas de différence significative dans les scores de douleur entre les deux groupes, mais les scores de douleur avec les deux échelles de douleur étaient significativement plus élevés (p < 0,001 pour les deux) six heures par rapport à une et 20 heures postopératoires. La valeur seuil des échelles de douleur (nécessitant une analgésie de secours) a été dépassée dans 34,5 % des cas pour le mGCPS et dans 39,5 % des cas pour le mCSU. Les chats ayant un score de douleur plus élevé ont présenté une prise alimentaire plus faible (p < 0,001). L'administration intrapéritonéale de ropivacaïne n'a pas amélioré significativement l'analgésie par rapport à une solution saline intrapéritonéale. La combinaison anesthésique couramment utilisée en pratique pour la stérilisation (médétomidine, kétamine, butorphanol), complétée par des médicaments analgésiques non stéroïdiens supplémentaires, a entraîné une analgésie postopératoire insuffisante 6 heures après la chirurgie chez plus d'un tiers des chats étudiés.

High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells.

PURPOSE: We investigated the autophagic response of rat Müller rMC-1 cells during a short-term high glucose challenge. METHODS: rMC-1 cells were maintained in 5 mM glucose (LG) or exposed to 25 mM glucose (HG). Western blot analysis was used to evaluate the expression levels of markers of autophagy (LC3-II, p62) and glial activation (AQP4), as well as the activation of TRAF2/JNK, ERK and AKT pathways. Autophagic flux assessment was performed using the autophagy inhibitor chloroquine. ROS levels were measured by flow cytometry using dichlorofluorescein diacetate. ERK involvement in autophagy induction was addressed using the ERK inhibitor FR180204. The effect of autophagy inhibition on cell viability was evaluated by SRB assay. RESULTS: Activation of autophagy was observed in the first 2-6 h of HG exposure. This early autophagic response was transient, not accompanied by an increase in AQP4 or in the phospho-activation of JNK, a key mediator of cellular response to oxidative stress, and required ERK activity. Cells exposed to HG had a lower viability upon autophagy inhibition by chloroquine, as compared to those maintained in LG. CONCLUSION: A short-term HG challenge triggers in rMC-1 cells a process improving the ability to cope with stressful conditions, which involves ERK and an early and transient autophagy activation.

Adherence to Guideline Recommendations for Perioperative Chemotherapy in Patients with pN2-3 M0 Squamous Cell Carcinoma of the Penis: Temporal Trends and Survival Outcomes.

AIMS: To analyse contemporary perioperative chemotherapy (CHT) guideline adherence rates for pN2-3 M0 squamous cell carcinoma of the penis, as well as CHT association with cancer-specific (CSM) and other-cause mortality (OCM). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results databases, 311 pN2-3 M0 squamous cell carcinoma of the penis patients treated with inguinal lymph node dissection were identified. Univariable and multivariable logistic regression analyses focused on CHT rates, whereas cumulative incidence plots and multivariable competing risks regression analyses tested for CSM and OCM rates. RESULTS: CHT was administered to 140 (45%) patients and rates increased from 37.5 to 62.2% (2004-2015; P = 0.02). Specifically, annual CHT rates increased over time in patients younger or equal to 65 years and in patients older than 65 years (44.4-84.6% versus 28.6-50%, respectively), but this trend was not statistically significant (P = 0.1 and P = 0.2, respectively). The median follow-up was 13 months for both CHT (interquartile range 8.0-32.2) and no-CHT subgroups (interquartile range 5.0-40.0). In multivariable logistic regression analyses, more contemporary year of diagnosis interval (odds ratio 2.08, P < 0.01) and age older than 75 years (odds ratio 0.14, P < 0.001) were independent predictors of CHT use. In multivariable competing risks regression analyses, CHT use did not affect CSM (hazard ratio 1.02; P = 0.7) or OCM (hazard ratio 1.56; P = 0.8). CONCLUSIONS: CHT adherence rates sharply increased in the most recent years. Despite this increase over time, the lack of efficacy regarding CSM benefit is disappointing.

Bi-layered collagen nano-structured membrane prototype collagen matrix CM-10826 for oral soft tissue regeneration: an in vivo ultrastructural study on 13 patients.

A new developed collagen matrix CM-10826 (CM) of porcine origin designed to be used as oral soft tissue substitute was investigated before and after implantation by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). In a case series biopsy specimens were harvested from thirteen patients at 10, 20, 30, 43 days after abutment surgery for uncovering dental implants. The in vivo histological evaluations of each patient were performed via micro-coring of newly formed oral mucosa in the area covered by CM (test side) or left uncovered (control). Results showed that CM can be integrated in connective and epithelial tissues within 10 days, can be completely resorbed within 20 days and it is able to reduce inflammatory infiltrates and to stimulate both fibroblast/epithelial cell proliferation and neo-angiogenesis. Generally it seems to be superior in promoting soft tissue healing compared to that induced by secondary intention healing. Furthermore, it is able to act as a scaffold for soft-tissue regeneration, allowing the proliferation of keratinocytes from the wound edges and favoring neovascularization and growth of connective tissue in the mesh of porous layer. It appears that a CM might function in oral surgery as a substitute for autologous grafts and to avoid secondary intention healing in soft tissue defects.

Robot-assisted Partial Nephrectomy and Bilateral Pyelolithotomy in Ectopic Pelvic Kidneys.

OBJECTIVE: To show how to perform a robot-assisted partial nephrectomy and bilateral pyelolithotomy in ectopic pelvic kidneys. This is a congenital abnormality of position and rotation1 frequently associated with urolithiasis.2 Renal cell carcinoma is a very rare event in pelvic kidneys.3,4 These 2 findings in the same patient could be a surgical challenge and whenever possible a "one stage" treatment is preferred. MATERIALS AND METHODS: A 44-year-old male with bilateral pelvic kidneys admitted because of left back pain. Abdominal CT scan showed a 17 mm stone in the left renal pelvis, a 12 mm stones in the right pelvis and a 34 × 27 mm right lower pole renal mass. A robotic surgery was indicated. Patient was placed in Trendelenburg position with ports configuration as for transperitoneal radical prostatectomy. The right kidney was firstly approached: after isolation of the ureter and suspension of the renal artery, a clampless partial nephrectomy was performed; then through a longitudinal pyelotomy the stone was extracted. To minimize the opening of the posterior peritoneum covering the left kidney, the site of the stone was identified by intraoperative ultrasound; then, through a longitudinal pyelotomy the stone was extracted. Given the watertight sutures and the lack of ureteral obstructions no pigtails ureteral catheters were inserted. A Jackson-Pratt drainage was placed through the inferior port. RESULTS: Consolle time was 190 minutes. Estimated Blood Loss (EBL) was 50 ml. No complications were reported. The drain was removed on the second postoperative day, assessed that creatinine dosage was equal to serum. The length of stay was 4 days. Histopathology showed a pT1a G2 clear cell renal cell carcinoma with negative surgical margins, while stones analysis was calcium oxalate. CONCLUSION: With the availability of robotic technology, the indications for minimally invasive surgery may be safely expanded to include concomitant morbidities in uncommon presentations.

To which countries do European psychiatric trainees want to move to and why?

BACKGROUND: There is a shortage of psychiatrists worldwide. Within Europe, psychiatric trainees can move between countries, which increases the problem in some countries and alleviates it in others. However, little is known about the reasons psychiatric trainees move to another country. METHODS: Survey of psychiatric trainees in 33 European countries, exploring how frequently psychiatric trainees have migrated or want to migrate, their reasons to stay and leave the country, and the countries where they come from and where they move to. A 61-item self-report questionnaire was developed, covering questions about their demographics, experiences of short-term mobility (from 3 months up to 1 year), experiences of long-term migration (of more than 1 year) and their attitudes towards migration. RESULTS: A total of 2281 psychiatric trainees in Europe participated in the survey, of which 72.0% have 'ever' considered to move to a different country in their future, 53.5% were considering it 'now', at the time of the survey, and 13.3% had already moved country. For these immigrant trainees, academic was the main reason they gave to move from their country of origin. For all trainees, the overall main reason for which they would leave was financial (34.4%), especially in those with lower (<500€) incomes (58.1%), whereas in those with higher (>2500€) incomes, personal reasons were paramount (44.5%). CONCLUSIONS: A high number of psychiatric trainees considered moving to another country, and their motivation largely reflects the substantial salary differences. These findings suggest tackling financial conditions and academic opportunities.

Bi-layered collagen nano-structured membrane prototype collagen matrix 10826® for soft tissue regeneration in rabbits: an in vivo ultra-structural study of the early healing phase.

Collagen Matrix (CM) 10826 is a nanostructured bi-layered collagen membrane obtained from type I and III porcine collagen, which in vitro has shown to have the potential to be a substitute and/or stimulant for soft oral tissue regeneration. The objective of this study was to evaluate the in vivo potential and safety of this membrane for soft tissue regeneration in the early stage of wound healing. Two soft tissue wounds (test and control) were created on the back skin of 5 rabbits (female New Zealand White Rabbits specific pathogen free). All wounds were protected by a special poly-tetra-fluoro-ethylene (PTFE) healing camera. On each rabbit on the test side CM-10826 was used, while on the control side conventional treatment (an autologous pedicle graft) was performed. The healing process was observed clinically after 2 and 6 days, and Magnetic Resonance Imaging (MRI) was performed after this period. After 7 days, animals were sacrificed and specimens were analyzed with light optic microscopy (LM), Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). These in vivo trials on rabbits confirmed that CM-10826 is well tolerated, without signs of histological inflammatory reaction and proved to be able to accelerate the spontaneous repair of the skin defect taken as the control. The light-optic and ultra-microscopy of serial biopsies showed that the new matrix is biocompatible and is able to function as a scaffold inducing soft tissue regeneration. In conclusion this study demonstrates that CM-10826 promote early soft tissue regeneration and suggests it is a potential constituent for human autologous keratinocytes seeded derma bioequivalent. It protects the wound from injuries and bacterial contamination accelerating healing process. As a clinical relevance, we consider that the quality of life of patients will be improved avoiding the use of major autologous grafts, reducing the hospitalization time and morbidity.

Pharmaceutical industry interactions of psychiatric trainees from 20 European countries.

BACKGROUND: Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees. METHODS: One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire. RESULTS: The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean)=0.92, SD=1.44, range=0-12) and most in Portugal (M=19.06, SD=17.44, range=0-100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M=3.30, SD=1.26 vs. M=2.39, SD=1.06 on a 5-point Likert scale: 1 "completely disagree" to 5 "completely agree"). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio)=1.21, 95%CI=1.12-1.30 and OR=1.18, 95%CI=1.02-1.37). CONCLUSIONS: There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training.

The fine-tuning of TRAF2-GSTP1-1 interaction: effect of ligand binding and in situ detection of the complex.

We provide the first biochemical evidence of a direct interaction between the glutathione transferase P1-1 (GSTP1-1) and the TRAF domain of TNF receptor-associated factor 2 (TRAF2), and describe how ligand binding modulates such an equilibrium. The dissociation constant of the heterocomplex is K(d)=0.3 µM; however the binding affinity strongly decreases when the active site of GSTP1-1 is occupied by the substrate GSH (K(d)≥2.6 µM) or is inactivated by oxidation (Kd=1.7 µM). This indicates that GSTP1-1's TRAF2-binding region involves the GSH-binding site. The GSTP1-1 inhibitor NBDHEX further decreases the complex's binding affinity, as compared with when GSH is the only ligand; this suggests that the hydrophobic portion of the GSTP1-1 active site also contributes to the interaction. We therefore hypothesize that TRAF2 binding inactivates GSTP1-1; however, analysis of the data, using a model taking into account the dimeric nature of GSTP1-1, suggests that GSTP1-1 engages only one subunit in the complex, whereas the second subunit maintains the catalytic activity or binds to other proteins. We also analyzed GSTP1-1's association with TRAF2 at the cellular level. The TRAF2-GSTP1-1 complex was constitutively present in U-2OS cells, but strongly decreased in S, G2 and M phases. Thus the interaction appears regulated in a cell cycle-dependent manner. The variations in the levels of individual proteins seem too limited to explain the complex's drastic decline observed in cells progressing from the G0/G1 to the S-G2-M phases. Moreover, GSH's intracellular content was so high that it always saturated GSTP1-1. Interestingly, the addition of NBDHEX maintains the TRAF2-GSTP1-1 complex at low levels, thus causing a prolonged cell cycle arrest in the G2/M phase. Overall, these findings suggest that a reversible sequestration of TRAF2 into the complex may be crucial for cell cycle progression and that multiple factors are involved in the fine-tuning of this interaction.

Risk of burnout among early career mental health professionals.

Burnout is a stress-related syndrome that often affects mental health professionals (MHPs) and may have serious consequences on personal well-being as well as on the quality of provided psychiatric care. Established literature shows a high risk to develop burnout among MHPs. Few data are available on the incidence and on the clinical implications of the burnout syndrome in the early phases of MHP professional career. We confirmed the presence of burnout among early career MHPs: early career psychiatrists showed a lower sense of personal accomplishment, while non-medical MHPs tended to have more depersonalization and suffered from higher levels of depression. Specific programmes to identify the presence of the burnout syndrome and to cope with it should be taught within mental health training curricula. Burnout is a stress-related syndrome that often affects professionals working in emotionally loaded and highly interpersonal environments. Mental health professionals (MHPs) are long known to be at high risk to develop the burnout syndrome, but this has rarely been investigated in professionals in an early phase of career. The aim of the present study was to evaluate the presence of the burnout syndrome and of depressive symptoms among early career psychiatrists and 'non-medical' MHPs. One hundred MHPs (including 50 psychiatrists and 50 non-medical MHPs) were screened for the presence of burnout and depression, with the Maslach Burnout Inventory and the Beck Depression Inventory - revised, respectively. The relationships of burnout with socio-demographical and professional characteristics were also explored. We confirmed the presence of burnout among both groups of early career MHPs, but psychiatrists had a significantly higher degree of emotional exhaustion and a lower sense of personal accomplishment, while non-medical MHPs adopted more frequently depersonalization as a coping strategy and had higher scores for depression, which is associated with higher level of burnout. The risk of developing burnout should be properly addressed in training curricula and strategies to overcome it should be systematically taught, in order to promote personal well-being and efficient team work in mental health settings.

Curcumin induces apoptosis in breast cancer cell lines and delays the growth of mammary tumors in neu transgenic mice.

Breast cancer is a leading cancer in women and despite the benefits of the current therapies a significant number of patients with this tumor is at risk of relapse. Some of the alterations taking place in breast cancer cells are currently exploited by molecularly targeted drugs. Different drugs have been developed which target a single molecule but, given that the tumor originates from the dysregulation of many genes, there is the need to find new drugs that have more than one molecular target. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] (CUR), a polyphenolic compound found in the spice turmeric, is a pleiotropic molecule able to interact with a variety of molecular targets and has antitumor, anti-inflammatory, antioxidant, immunomodulatory and antimicrobial activities. Here we demonstrate that CUR inhibits the growth of breast cancer cell lines in a dose dependent manner, with IC50 values in the micromolar range, and induces an increase in the percentage of cells in sub-G0 phase, representing the apoptotic cell population. The activation of apoptosis was confirmed by PARP-1 cleavage and by the increased ratio between the pro-apoptotic Bax and the anti-apoptotic Bcl-2 protein. In addition, in CUR-treated cells the activity of ERK1/ERK2 MAP kinases was down-regulated. The cytotoxic effects of CUR were observed in breast cancer cells expressing either high or low levels of ErbB2/neu. The in vivo antitumor activity of CUR was tested in BALB-neuT mice transgenic for the neu oncogene, which develop atypical hyperplasia of the mammary gland at 6 weeks of age and invasive carcinoma at 16 weeks of age. CUR, administered to mice both early and in an advanced stage of mammary carcinogenesis, induced a significant prolongation of tumor-free survival and a reduction of tumor multiplicity. In addition, CUR administration was safe, since no modification of hematological and clinical chemistry parameters could be observed in BALB-neuT and BALB/c mice treated with this compound for several weeks. These findings support further studies on the therapeutic potential of CUR in combination with standard therapies in breast cancer patients.

Application of poly-L-lactide screws in flat foot surgery: histological and radiological aspects of bio-absorption of degradable devices.

The flat foot in childhood is a condition frequently observed in orthopedic practice but it is still debated when and in which patients surgical corrective treatment is appropriate; recently, the application of poly-L-lactic-acid (PLLA) screws was proposed. The present study investigates a group of 33 patients treated with PLLA expansion endorthesis in order to evaluate the deformity correction. Clinical and radiological outcomes in patients were correlated with: a) morphological characterization of screws both before and after being removed from patients, when necessary; b) histological and bio-molecular evaluation of degradation processes of the implants, focusing attention on the correlation between the cellular cohort involved in inflammatory reaction and the bio-absorption degree of PLLA screws. Deformity correction was mostly achieved, with minimal need of screw removal; the results obtained clearly show the occurrence of chronic rather than acute inflammation in removed screw specimens. At the histological level, after biomaterial implantation, the sequence of events occurring in the surrounding tissues ultimately ends in the formation of foreign body giant cells (FBGCs) at the tissue/material interface; but the mechanisms which influence the fate of screw implants, i.e. the resolution of acute inflammation rather than the progression towards chronic inflammation, are of crucial importance for biodegradable materials like "polylactic acid". In fact, the FBGC response ensures a long-term mechanism which eliminates the foreign material from the body, but at the same time the implications of prolonged FBGC responses, which generate negative side effects, could significantly impede the healing progress.

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation.

The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.

OBJECTIVE: Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline. METHODS: A total of 1,352 participants without dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later. RESULTS: Hypertension in midlife was associated with accelerated WMHV progression (p < 0.001) and worsening executive function (TrB-A score; p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy (p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume (p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 [95%confidence interval 1.07-2.33], p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 [1.02-1.88], p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 [1.44-81.01], p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function. CONCLUSIONS: Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.

Placenta growth factor is a survival factor for human malignant mesothelioma cells.

Placenta growth factor (PlGF) is a key regulator of pathological angiogenesis and its overexpression has been linked to neoplastic progression. To assess whether PlGF could have a role in malignant mesothelioma (MM), we analyzed the expression of PlGF, VEGF, and their cognate receptors (VEGF-R1 and VEGF-R2) and co-receptors (neuropilin-1 and neuropilin-2) in MM cell lines as well as in resected MM tissues, hyperplastic/reactive mesothelium and normal mesothelium. MM cell cultures expressed both ligands and the associated receptors to a variable extent and released different amounts of PlGF. As assessed by immunohistochemistry, PlGF expression was switched on in hyperplastic/reactive compared to normal mesothelium. Moreover, 74 and 94 percent of MM tissues overexpressed PlGF and VEGF-R1, respectively (p<0.05 MM vs normal mesothelium). Administration of recombinant PlGF-2 did not elicit a significant stimulation of MM cell growth, while it was associated with a transient phosphorylation of Akt, suggesting that PlGF-2 could activate downstream effectors of proliferative and cytoprotective signals via VEGF-R1 in MM cells. Indeed, the administration of an anti-PlGF antibody was found to cause a significant reduction of MM cell survival. In conclusion, our data demonstrate that, by acting as a survival factor, PlGF can play a role which goes beyond the stimulation of angiogenesis in MM. This evidence could help the rational design of new therapeutic interventions for this aggressive tumor.