A Cluster Analysis of Neuropsychological Impairment in Borderline Personality Disorder: Identifying a Neurocognitive Subtype Linked to Attention Deficit Hyperactivity Disorder.

INTRODUCTION: Cognitive impairment associated with borderline personality disorder (BPD) has been consistently demonstrated. However, a specific neuropsychological profile has not yet been established for this disorder, maybe due to the heterogeneity of BPD. The aim of this work is the search for distinct neuropsychological subtypes among patients with BPD and for the association of neuropsychological subgroups with specific clinical characteristics. METHODOLOGY: One hundred fifteen patients with BPD diagnosis received an extensive neuropsychological evaluation assessing attentional, memory and executive functions indexes. For subtyping strategies, a cluster analysis of neuropsychological BPD distribution was performed. Central clinical dimensions of BPD were measured and analysed in relation with the obtained neuropsychological clusters. RESULTS: Two clusters were found: Cluster 1 showed a significantly lower score on the working memory index, and Cluster 2 had significantly worse overall executive performance, response inhibition and planning abilities. Patients in the neurocognitive Cluster 2 showed significantly higher clinical deficits of attention as measured with subscales of the CAARS attention deficit hyperactivity disorder (ADHD) index (F = 2.549, p < 0.005, d = 11.49). CONCLUSIONS: Two neuropsychological clusters of patients were found in the BPD sample: Cluster 1 patients showed greater impairment in working memory, while Cluster 2 patients had greater deficits of executive functioning, particularly for response inhibition and planning. In addition, BPD patients with greater executive deficits presented greater levels of ADHD clinical features. These findings might also facilitate earlier diagnosis of severe BPD patient profiles and to establish more personalized treatment based on neurocognitive stimulation.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Bone turnover markers are decreased in GC-treated subjects with DM. Decreased OC levels in GC-treated patients were associated with an increased risk of DM. These results suggest the involvement of OC in glucose homeostasis regulation in DM. INTRODUCTION: Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. METHODS: One hundred twenty-seven patients (aged 61.5 ± 17.9 years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. RESULTS: Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25 ng/mL for OC, < 24 ng/mL for PINP, < 27.5 nMol/mM for NTX and < 0.25 ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). CONCLUSION: Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Decreased oxytocin plasma levels and oxytocin receptor expression in borderline personality disorder.

INTRODUCTION: Borderline personality disorder (BPD) is characterized by intense affective reactions with underlying social and interpersonal cognitive deficits. Oxytocin has largely been associated with both stress regulation and social cognition in psychiatric patients and in non-clinical populations in previous studies. Finally, abnormal oxytocin levels have been preliminary reported in BPD patients. METHODS: 53 patients with moderate-severe BPD and 31 healthy control subjects were investigated for plasma levels of oxytocin and protein expression of oxytocin receptor in blood mononuclear cells. Clinical assessments were made for severity, functionality, and comorbidity with axis I and II conditions. RESULTS: Oxytocin plasma levels were significantly lower in BPD patients compared with controls. In addition, protein expression of oxytocin receptor was significantly reduced in the BPD group. A positive correlation was found between plasma oxytocin levels and the activity index score of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). Oxytocin receptor protein expression, on the contrary, had a negative correlation with the ZKPQ sociability index score. CONCLUSIONS: Results support the evidence of a dysfunction of the oxytocin system in borderline personality disorder, which could be involved in emotional dysregulation and interpersonal disturbances in these patients.

Effect of recent spinal cord injury on the OPG/RANKL system and its relationship with bone loss and the response to denosumab therapy.

There is marked bone loss after spinal cord injury (SCI); however, its pathogenesis and clinical management remain unclear. The increased circulating levels of receptor activator of nuclear factor kB ligand (RANKL) associated with bone loss shortly after SCI and the prevention of bone loss with denosumab treatment suggest a contributory role of RANKL in SCI-induced osteoporosis. INTRODUCTION: Bone turnover and bone loss are markedly increased shortly after SCI. However, the pathogenesis and clinical management of this process remain unclear, especially the role of the osteoprotegerin (OPG)/RANKL system in this disorder. The aim of this study was to analyze serum levels of OPG and RANKL in bone loss associated with recent SCI and the effect of denosumab treatment on these mediators. METHODS: Twenty-three males with recent complete SCI were prospectively included. Serum OPG and RANKL levels, bone turnover markers (PINP, bone ALP, CTX), and bone mineral density (BMD) were assessed at baseline, at 6 months of follow-up, prior to initiating denosumab, and 6 months after treatment. The results were compared with a healthy control group. RESULTS: At baseline, SCI patients showed higher RANKL levels vs. controls which were correlated with days-since-SCI and total hip BMD loss at 6 months. OPG levels were similar to controls at baseline. After denosumab treatment, OPG showed no changes, whereas RANKL levels became undetectable in 67% of patients. Patients with undetectable RANKL during treatment showed better response in femoral BMD and bone markers vs. patients with detectable RANKL at 6 months of denosumab. Increased parathormone (PTH) levels during treatment were negatively correlated with RANKL changes. CONCLUSIONS: RANKL levels are increased after SCI and related to BMD loss at the proximal femur, becoming undetectable after denosumab treatment. The effect of denosumab on preventing sublesional bone loss, especially in patients with undetectable levels during treatment, suggests a contributory role of RANKL in this process.

Comparison of total, free and bioavailable 25-OH vitamin D determinations to evaluate its biological activity in healthy adults: the LabOscat study.

Determination of different forms of 25-OHD (total, free and bioavailable) in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency. INTRODUCTION: Determination of 25-OH vitamin D serum levels (25-OHD) constitutes the method of choice for evaluating vitamin D deficiency. However, vitamin D-binding protein (DBP) may modulate its bioavailability thereby affecting correct evaluation of 25-OHD status. We analysed the impact of the determination of 25-OHD (total, free and bioavailable) on the evaluation its biologic activity (estimated by serum PTH determination) in healthy young women. METHODS: 173 premenopausal women (aged 35-45 yrs.) were included. We analysed serum values of total 25-OHD (25-OHDT), DBP, albumin, PTH and bone formation (PINP,OC) and resorption (NTx,CTx) markers. Free(25-OHDF) and bioavailable (25-OHDB) serum 25-OHD levels were estimated by DBP and albumin determinations and also directly by ELISA (25-OHDF-2). We analysed threshold PTH values for the different forms of 25-OHD and the correlations and differences according to 25-OHDT levels <20 ng/ml. RESULTS: 62% of subjects had 25-OHD values <20 ng/ml and also had significantly lower 25-OHDF and 25-OHDB values, with no significant differences in bone markers and PTH values. The PTH threshold value was similar for all forms of 25-OHD (∼70 pg/ml). Women with PTH values >70 had lower 25-OHDT (15.4 ± 1.4 vs. 18.3 ± 2.7, p < 0.05) and 25OHDB values (1.7 ± 0.2 vs. 2.2 ± 0.09, p < 0.05). The different forms of 25OHD were significantly intercorrelated, with marginal correlations between PTH and 25-OHDT (r = -0.136, p = 0.082). CONCLUSIONS: Determination of different forms of 25-OHD in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency.

Denosumab increases sublesional bone mass in osteoporotic individuals with recent spinal cord injury.

UNLABELLED: Osteoporosis is a frequent complication related to spinal cord injury (SCI), and data on osteoporosis treatment after SCI is scarce. Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis. INTRODUCTION: Osteoporosis development is a frequent complication related to SCI, especially at the sublesional level. Nevertheless, data on osteoporosis treatment after SCI is scarce, particularly short term after injury, when the highest bone loss is produced. The aim of this study was to analyze the efficacy of denosumab in the treatment of SCI-related osteoporosis. METHODS: Fourteen individuals aged 39 ± 15 years with osteoporosis secondary to recent SCI (mean injury duration 15 ± 4 months) were treated with denosumab for 12 months. Bone turnover markers (BTMs) (PINP, bone ALP, sCTx), 25-hydroxyvitamin D (25OHD) levels and bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were assessed at baseline and at 12 months. All participants received calcium and vitamin D supplementation. RESULTS: At 12 months, SCI denosumab-treated participants showed a significant increase in BMD at TH (+2.4 ± 3.6 %, p = 0.042), FN (+3 ± 3.6 %, p = 0.006), and LS (+7.8 ± 3.7 %, p < 0.001) compared to baseline values. Denosumab treatment was associated with significant decreases in BTMs (bone ALP -42 %, p < 0.001; PINP -58 %, p < 0.001, sCTx -57 %, p = 0.002) at 12 months. BMD evolution was not related to BTM changes or 25OHD serum levels. No skeletal fractures or serious adverse events were observed during follow-up. CONCLUSIONS: Treatment with denosumab increases lumbar and femoral BMD and decreases bone turnover markers in individuals with recent SCI. This drug may be a promising therapeutic option in SCI-related osteoporosis.

Risk factors for the development of osteoporosis after spinal cord injury. A 12-month follow-up study.

UNLABELLED: Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis. The evaluation of bone mineral density shortly after SCI is a simple and effective method for predicting the development of osteoporosis during the first year after SCI. INTRODUCTION: Spinal cord injury (SCI) has been associated with a marked bone loss after injury and a consequent increased risk of osteoporosis and fractures. The aim of this study was to analyze the factors associated with osteoporosis development short-term after SCI. METHODS: We included patients with complete recent SCI (<6 months) evaluating bone turnover markers (P1NP, bone ALP, and sCTx), 25-OH-vitamin D (25OHD) levels, and lumbar and femoral BMD (Lunar, Prodigy) at baseline, 6 and 12 months after SCI. The risk factors for osteoporosis analyzed included the following: age, gender, BMI, toxic habits, bone turnover markers, 25OHD levels, lumbar and femoral BMD, level, severity and type of SCI, and days-since-injury. Osteoporosis was defined according to WHO criteria. RESULTS: Thirty-five patients aged 35 ± 16 years were included, and 52 % developed osteoporosis during the 12-month follow-up. These latter patients had lower BMD values at femur and lumbar spine and higher bone turnover markers at baseline. On multivariate analysis, the principal factors related to osteoporosis development were as follows: total femur BMD <1 g/cm(2) (RR, 3.61; 95 % CI 1.30-10.06, p = 0.002) and lumbar BMD <1.2 g/cm(2) at baseline (0.97 probability of osteoporosis with both parameters under these values). Increased risk for osteoporosis was also associated with increased baseline values of bone ALP (>14 ng/mL) (RR 2.40; 95 % CI 1.10-5.23, p = 0.041) and P1NP (>140 ng/mL) (RR 3.08; 95 % CI 1.10-8.57, p = 0.017). CONCLUSIONS: The evaluation of BMD at the lumbar spine and femur short-term after SCI is a simple, effective method for predicting the development of osteoporosis during the first year after SCI. Our results also indicate the need to evaluate and treat these patients shortly after injury.

Mentalizing deficits in borderline personality disorder related to axis I comorbidity: Clinical relevance.

AIM: Deficits in mentalization have been described in several mental disorders, but information is still scarce and ambiguous about the types of mentalization errors in each disorder and their specificity and severity in borderline personality disorder (BPD). Due to the high comorbidity between this disorder and axis I disorders, the aim of this work is to study differences in mentalization responses in BPD considering the different comorbidity profiles with other disorders. METHODS: A total of 141 BPD patients were evaluated using The Mini-International Neuropsychiatric Interview (MINI), to identify comorbid axis I disorders. Mentalizing ability was assessed by the Movie for the Assessment of Social Cognition (MASC). Statistical associations were analysed into the different variables. RESULTS: Patients with comorbid BPD and anorexia nervosa (AN), suicidal behaviour disorder or post-traumatic stress disorder (PTSD) respectively presented higher overmentalization, undermentalization and absence of mentalization errors, compared with patients with BPD without comorbidity. CONCLUSIONS: Results show that BPD comorbidity with AN, suicidal behaviour disorder and PTSD affect to the types and severity of mentalizing deficits observed in these patients. This study highlights the importance of the assessment and treatment of axis I comorbid disorders in borderline personality disorder, with the objective of shaping personalized treatment for every patient.

"Vascular tuft sign" in neuroendocrine tumors of the pancreas.

The often well-developed microvasculature in pancreatic neuroendocrine tumors (PanNETs) has been studied from different perspectives. However, some detailed structural findings have received less attention. Our objective is to study an overlooked event in PanNETs: "enclosed vascular tufts" (EVTs). For this purpose, 39 cases of PanNETs were examined with conventional (including serial sections) and immunochemistry procedures. In typical EVTs, the results show: 1) an insulated terminal vascular area, with a globular (glomeruloid) aspect, formed by a cluster of coiled microvessels, presenting CD31-, CD34-positive endothelial cells, αSMA-positive pericytes, and perivascular CD34-positive stromal cells/telocytes, separated by a pseudoglandular space from the surrounding trabeculae of tumor neuroendocrine cells; and 2) a pedicle joining the insulated terminal vascular area, with connective tissue tracts around the enclosing tumor trabeculae. EVTs predominate in the trabecular and nested gyriform pattern of PanNETs, with tumor trabeculae that follow a ribbon coil (winding ribbon pattern) around small vessels, which acquire a tufted image. In EVTs, secondary modifications may occur (fibrosis, hyalinization, myxoid changes, and calcification), coinciding or not with those of the connective tracts. In conclusion, the typical characteristics of unnoticed EVTs allow them to be considered as a morphological sign of PanNETs (a vascular tuft sign). Further in-depth studies are required, mainly to assess the molecular pathways that participate in vascular tuft formation and its pathophysiological implications.

Decreased oxytocin plasma levels and oxytocin receptor expression associated with aggressive behavior in aggressive-impulsive disorders.

INTRODUCTION: This study aims to enhance the understanding of the association between the phenotypic and endophenotypic characteristics of impulsive-aggressive disorders, through the study of plasma oxytocin (OXT) and oxytocin receptor (OXTR) levels in patients with borderline personality disorder (BPD) and patients with eating disorders (ED), as well as to examine the relationship of OXT system with aggressive behavior in these disorders. METHODS: 68 patients with BPD, 67 patients with ED and 57 healthy control subjects were examined for plasma oxytocin levels and protein expression of OXTR in blood mononuclear cells. Aggressive behavior was assessed using the State-Trait Anger Expression Inventory (STAXI-2). Other self and hetero-aggressive behaviors were also evaluated through interviews. RESULTS: BPD and ED patients exhibited significantly lower plasma oxytocin levels than control subjects. Furthermore, BPD patients demonstrated significantly reduced expression of OXTR compared to controls. Plasma oxytocin levels negatively correlated with verbal aggression, while OXTR expression was inversely associated with the STAXI trait subscale. CONCLUSIONS: The findings validate the existence of oxytocin system dysfunction in impulsive-aggressive disorders. They also support the link between low OXT levels in plasma and OXTR expression and the impulsive-aggressive behavior that characterizes these patients in both state and trait situations.

Transdiagnostic inflammatory and oxidative biomarkers with predictive capacity of self-injurious behavior in impulsive and unstable disorders.

INTRODUCTION: Alterations in inflammatory processes have previously been reported in impulsive and unstable disorders, as well as in other psychiatric conditions. In order to investigate transdiagnostic biomarkers associated with various phenotypic features of these disorders, this study is designed to identify biomarkers of inflammatory and oxidative endophenotypes related to autolytic behavior. METHODS: Peripheral blood mononuclear cells were collected from 35 patients with borderline personality disorder (BPD), 29 patients with restrictive eating disorder (rED), 21 patients with purging eating disorder (pED) and 23 control subjects. Plasma levels of different inflammatory and oxidative factors were measured by ELISA and the expression of selected proteins was by Western Blot. Principal component analysis (PCA) was performed to categorize the different inflammatory factors. Additionally, Ancova was performed to observe the differences in the principal components among the different groups and logistic regression analysis was conducted to assess the predictive capacity of these components for autolytic behaviors. RESULTS: We found two inflammatory/oxidative components were associated with BPD, characterized by high levels of JNK and ERK and low levels of GPx, SOD and Keap1; and two other inflammatory/oxidative components were linked to pED, associated with more JNK, TBARS and TNF-α and less GPx and SOD. Two components, with more JNK and ERK and less GPx, SOD and Keap1, predicted non-suicidal self-injury and three components, with higher JNK, TBARS and TNF-α levels and lower GPx, SOD and iNOS levels, predicted suicide attempts. CONCLUSIONS: These results strongly support the endophenotypic characterization of impulsivity and the identification of transdiagnostic inflammatory/oxidative biomarkers relevant to autolytic behavior in impulsive and unstable disorders. These dates lay the groundwork for developing of screening tests for these biomarker components to rapidly detect biological risk factors for specific impulse control disorders and future self-injurious behaviors.

Inflammatory and oxidative endophenotypes in borderline personality disorder: A biomarker cluster analysis.

OBJECTIVES: This study is designed to search for aggrupation of inflammatory/oxidative biomarker alterations in borderline personality disorder (BPD) and their association with phenotypic features. METHODOLOGY: Inflammatory/nitrosative proteins were measures in plasma and peripheral blood mononuclear cells obtained from BPD patients. Patients were assessed on different clinical dimensions of BPD. Oxidative damage was tested by measuring TBARS, nitrites, catalase, GPx and SOD. Protein expression of IκBα, NFκB, iNOS, COX-2, PPARγ, Keap1, NQO1, Nrf2 and α7nAChR was also determined. Western blot and ELISA were used for measurements and a cluster analysis of inflammatory/oxidative biomarkers alterations was performed to investigate subgroups of patients with similar alterations and its relationship with clinical features of BPD. RESULTS: 69 patients were included in the study. Two inflammatory/nitrosative clusters of patients were found: Cluster 1 patients showed significantly higher levels of GPx, IκBα, keap1, NQO1, PPARγ, α7nAChR and Nrf2 than cluster 2 patients. These patients had significantly longer duration of illness, milder anxiety symptoms and lower prescription of antipsychotic drugs than cluster 2. CONCLUSIONS: Two clusters of BPD patients according to the inflammatory/nitrosative profiles were identified. Cluster 1 had increased antioxidant and anti-inflammatory biomarkers and was characterised by greater chronicity of illness but less acute symptomatic severity.

Grit blasting of medical stainless steel: implications on its corrosion behavior, ion release and biocompatibility.

This study reports on the biocompatibility of 316 LVM steel blasted with small and rounded ZrO(2) particles or larger and angular shaped Al(2)O(3) particles. The effect of blasting on the in vitro corrosion behavior and the associated ion release is also considered. Surface of Al(2)O(3) blasted samples was rougher than that of ZrO(2) blasted samples, which was also manifested by a higher surface area. Compared to the polished alloy, blasted steels exhibited a lower corrosion resistance at the earlier stages of immersion, particularly when using Al(2)O(3) particles. With increasing immersion time, blasted samples experienced an improvement of the corrosion resistance, achieving impedance values typical of passive alloys. Blasting of the alloy led to an increase in Fe release and the leaching of Ni, Mn, Cr and Mo. On all surfaces, ion release is higher during the first 24 h exposure and tends to decrease during the subsequent exposure time. Despite the lower corrosion resistance and higher amount of ions released, blasted alloys exhibit a good biocompatibility, as demonstrated by culturing osteoblastic cells that attached and grew on the surfaces.

Corrosion behaviour and biocompatibility of a novel Ni-free intermetallic coating growth on austenitic steel by hot dipping in an Al-12.6%Si alloy.

Commercial 316 LVM austenitic stainless steel samples have been coated by immersion in a bath of molten Al-12.6%Si alloy for 120 s. The coating consists of the Al(12)(Fe,Cr)(3)Si(2) intermetallic. In vitro corrosion behaviour has been evaluated in the Ringer's solution by means of potentiodynamic curves and electrochemical impedance spectroscopy. The results reveal that the coated specimens exhibit lower susceptibility to localised corrosion with respect to the substrate. XPS analysis suggests that the ennoblement of the pitting potential is due to the formation of a chromium oxyhydroxide containing passive layer. The intermetallic coating shows a good biocompatibility, as demonstrated by culturing human mesenchymal stem cells isolated from bone marrow which attached, grew and differentiated to the osteoblastic lineage to a similar extent on coated and bare steels. In summary, this study proposes a method that generates Ni-free coatings of the stainless steel with useful properties for biomedical applications.

Differential gene expression analysis provides new insights into the molecular basis of iron deficiency stress response in the citrus rootstock Poncirus trifoliata (L.) Raf.

Iron chlorosis is one of the major abiotic stresses affecting fruit trees and other crops in calcareous soils and leads to a reduction in growth and yield. Usual remediation strategies consist of amending iron to soil, which is an expensive practice, or using tolerant cultivars, which are difficult to develop when not available. To understand the mechanisms underlying the associated physiopathy better, and thus develop new strategies to overcome the problems resulting from iron deficiency, the differential gene expression induced by iron deficiency in the susceptible citrus rootstock Poncirus trifoliata (L.) Raf. have been examined. The genes identified are putatively involved in cell wall modification, in determining photosynthesis rate and chlorophyll content, and reducing oxidative stress. Additional studies on cell wall morphology, photosynthesis, and chlorophyll content, as well as peroxidase and catalase activities, support their possible functions in the response to iron deficiency in a susceptible genotype, and the results are discussed.

Intussusceptive angiogenesis and its counterpart intussusceptive lymphangiogenesis.

Intussusceptive angiogenesis (IA) is currently considered an important alternative and complementary form of sprouting angiogenesis (SA). Conversely, intussusceptive lymphangiogenesis (IL) is in an initial phase of study. We compare their morphofunctional characteristics, since many can be shared by both processes. To that end, the following aspects are considered: A) The concept of IA and IL as the mechanism by which blood and lymphatic vessels split, expand and remodel through transluminal pillar formations (hallmarks of intussusception). B) Terminology and historical background, with particular reference to the group of Burri, including Djonov and Patan, who initiated and developed the vessel intussusceptive concept in blood vessels. C) Incidence in normal (e.g. in the sinuses of developing lymph nodes) and pathologic conditions, above all in vessel diseases, such as dilated veins in hemorrhoidal disease, intravascular papillary endothelial hyperplasia (IPEH), sinusoidal hemangioma, lobular capillary hemangioma, lymphangiomas/lymphatic malformations and vascular transformation of lymph nodes. D) Differences and complementarity between vessel sprouting and intussusception. E) Characteristics of the cover (endothelial cells) and core (connective tissue components) of pillars and requirements for pillar identification. F) Structures involved in pillar formation, including endothelial contacts of opposite vessel walls, interendothelial bridges, merged adjacent capillaries, vessel loops and spilt pillars. G) Structures resulting from pillars with intussusceptive microvascular growth, arborization, remodeling and segmentation (compartmentalization). H) Influence of intussusception in the morphogenesis of vessel tumors/ pseudotumors; and I) Hemodynamic and molecular control of vessel intussusception, including VEGF, PDGF BB, Hypoxia, Notch, Endoglobin and Nitric oxide.

Development of biocompatible and fully bioabsorbable PLA/Mg films for tissue regeneration applications.

During recent years, Mg reinforced polylactic acid (PLA) composites have emerged as potential biocompatible and bioabsorbable materials for biomedical applications. It has been shown that Mg particles added to a matrix based on a biodegradable polymer can address the lack of bioactivity and the low mechanical properties of the polymers and, furthermore, it can counteract the detrimental effects associated to the high degradation rate of Mg, as alkalinization and elevated H2 release. Additionally, the polymer can protect the Mg particles, by tailoring their degradation rate. Former processing of these composites performed by extrusion, compression and injection molding employed Mg contents up to 10 wt%. Higher amounts of Mg resulted in heterogeneous materials and thermally degraded matrices, with the corresponding higher degradation rate. In the present work, Mg reinforced PLA films with Mg content as high as 50 wt% were obtained without compromising the thermal stability of the polymer. Firstly, a successful dispersion of Mg microparticles was achieved by a breakthrough in processing introducing a colloidal step where organic additives were added to modify the Mg particle surface and promote a chemically stable suspension. The resulting colloidal suspension was then used as feedstock to obtain composite films by tape casting. The films show advantageous in vitro behaviour in terms of degradation, hydrogen release and oxygen permeability. In addition, the viability with fibroblast cells (MEF) opens a window of opportunity for these composite films as bioabsorbable material for tissue engineering and wound dressing applications. STATEMENT OF SIGNIFICANCE: Magnesium materials have extraordinary biodegradable properties and bioactive behavior due to release of Mg2+ ions, which offer a promising opportunity for their applicability as biomaterials for tissue regeneration. However, Mg is one of the most reactive metals with a high degradation rate. In contact with water produces H2, associated with a risk of failure of the implant. One alternative to minimize this drawback is the use of Mg particles surrounded by a biodegradable biocompatible polymer such as polylactic acid (PLA) to obtain PLA/Mg composites. In this work we processed Mg reinforced PLA in the shape of films that would be suitable for tissue regeneration. In vitro behavior of PLA/Mg films demonstrated that Mg2+ ions increase the fibroblast cells growth.

Evaluating average bioequivalence using methods for high variability drugs: a case study.

The purpose of this study was to determine if different methods for average bioequivalence in high variability drugs coincide or not in their conclusions when applied to the same dataset, and to discuss the method validity and reliability of the conclusions. Different approaches for the evaluation of average bioequivalence were applied to the results of a bioavailability trial on the diuretic drug Furosemide. These methods included widening the bioequivalence limits according to regulatory recommendations, scaling the limits and scaling the bioequivalence statistic, jointly with evaluating alternative bioavailability measures. The methods to establish the bioequivalence limits were also combined with some alternative methods to construct confidence intervals. The decision on bioequivalence depends much more on the bioavailability measures than on the statistical approach. The reliability of the final decision lies mainly in the interpretation of these measures and on the special characteristics of each drug.

Effect of UV irradiation on the surface Gibbs energy of Ti6Al4V and thermally oxidized Ti6Al4V.

Thermal oxidation of Ti6Al4V increases the thickness, modifies the structure, and changes the amount of alloying elements of the surface titanium dioxide layer with respect to the spontaneous passive layer of Ti6Al4V. The effects on the surface properties of Ti6Al4V and thermally oxidized Ti6Al4V after different periods of UV irradiation have been studied by measurement of water, formamide, and diiodomethane contact angles. The rate of modification of the water contact angle with the irradiation time is dependent on the surface treatment, but the water adhesion work, after an initial energetic step, follows a similar trend for both. Application of the Young equation together with the van Oss approach allowed evaluation of the surface Gibbs energy of the alloys. Similar to the water adhesion work, the surface Gibbs energy dependence on the irradiation time follows a similar trend for both samples and it is due to the change of the electron-donor parameter of the acid-base component. Also, a linear relationship common for both samples has been obtained between the cosines of the water contact angle and the formamide or diiodomethane contact angle. These facts indicate that the surface modification continuously produced by the UV irradiation is similar all along the process and similar for both samples after an energetic threshold for the thermally oxidized sample. It has been also tested that the hydrophilic-hydrophobic conversion is reversible for Ti6Al4V and Ti6Al4V thermally treated.