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.

Did the 2018 megadrought change the partitioning of growth between tree sizes and species? A Swiss case-study.

By killing or weakening trees, drought could change the partitioning of growth between tree sizes or species, thereby altering stand structure. Growth partitioning, often quantified using the growth dominance coefficient (DC) or the shape of tree size versus growth relationships (SGR), indicates the relative contribution of differently sized trees to the total stand growth. Changes in growth partitioning due to droughts are rarely examined but provide valuable information that links tree- and stand-level responses to droughts. The objective of this study was to test whether the 2018 European megadrought altered the growth partitioning among tree sizes and species. For this purpose, we first evaluated whether DC or SGR can be calculated from small sample sizes of trees typical of individual forest inventory plots. DC, and particularly SGR, were sensitive to sample size, forest type (even-aged and uneven-aged), target variable (tree diameter, basal area or stem mass) and range of tree sizes within the sample. SGR could therefore not be used for our analyses. We found no differences in DC prior to and during the 2018 drought. However, when considering only beech (Fagus sylvatica)-dominated stands, DC was lower during post-drought years than during the 2018 drought. The growth of larger trees, especially beech, was more negatively affected during post-drought years. Therefore, an extreme drought event can indeed alter the growth partitioning within forest stands. The DC indicates such changes in partitioning and, hence, which trees can be selected for commercial thinning, or released from competition, to minimize potential impacts of droughts.

Tratamiento farmacológico de la hipertensión arterial no severa durante el embarazo, el posparto y la lactancia / Pharmacological treatment of non-severe hypertension during pregnancy, postpartum and breastfeeding

La hipertensión arterial (HTA) en el embarazo se define como una presión arterial sistólica ≥ 140 y/o diastólica ≥ 90 mmHg. Con base en las cifras, se clasifica en no severa (< 160/110 mmHg) y severa (≥ 160/110 mmHg). Previamente a iniciar tratamiento en HTA no severa, se debe descartar HTA de bata blanca. Si es posible el manejo ambulatorio, se sugiere el inicio farmacológico ante valores sostenidamente elevados, evitando cifras < 120/80 mmHg. Los fármacos seguros durante la gestación son metildopa, labetalol y nifedipino-RETARD, pudiendo contemplarse el uso de nifedipino-OROS o amlodipino con menor nivel de evidencia. La utilización de diuréticos, atenolol y otros betabloqueadores con fines antihipertensivos no está recomendada en esta etapa. Los inhibidores del sistema renina-angiotensina-aldosterona están terminantemente contraindicados. En posparto y lactancia, puede mantenerse el mismo esquema terapéutico empleado durante el embarazo, intentando retirar la metildopa precozmente. Durante el puerperio, amlodipino y enalapril resultan seguros, con ínfima excreción por leche materna. (AU)

Hypertension (HTN) in pregnancy is defined as systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg. Based on the values, it is classified as non-severe (< 160/110 mmHg) and severe (≥ 160/110 mmHg). Before starting treatment in non-severe HTN, white- coat HTN should be ruled out. If outpatient management is possible, pharmacological initiation is suggested with sustained high values, avoiding < 120/80 mmHg. Safe drugs during pregnancy are methyldopa, labetalol, and nifedipine-retard. The use of nifedipine-XL or amlodipine can be considered with a lower level of evidence of safety. Diuretics, atenolol, and other beta-blockers for antihypertensive purposes is not recommended in this period. Renin-angiotensin-aldosterone system inhibitors are strictly contraindicated. In postpartum and breastfeeding, the same therapeutic regimen used during pregnancy can be maintained, trying early withdrawal of methyldopa. During puerperium, amlodipine and enalapril are safe, with minimal excretion in breast milk. (AU)

Influence of ultraconservative access cavities on instrumentation efficacy with XP-endo Shaper and Reciproc, filling ability and load capacity of mandibular molars subjected to thermomechanical cycling.

AIM: To evaluate the influence of ultraconservative access cavities (UltraAC) on canal shaping and filling ability and load capacity of mandibular molars after root canal preparation with XP-endo Shaper (XP) or Reciproc (RC), under simulated clinical conditions. Traditional access cavities (TradAC) were used for comparison. METHODOLOGY: Forty extracted mandibular molars were scanned by micro-computed tomographic and, based on similar anatomical features, were divided into four groups (n = 10), according to the type of access cavity and canal instrumentation protocol: TradAC/RC, TradAC/XP, UltraAC/RC and UltraAC/XP. All root canal procedures were performed with the teeth placed in a dental mannequin. Teeth were scanned after root canal instrumentation and filling. Unprepared canal area, dentine removed, accumulated hard tissue debris (AHTD), canal transportation, presence of voids and filling material remnants within the pulp chamber were analysed. After restorative procedures, the teeth were subjected to thermomechanical cycling and to a load capacity test. Statistical analyses were performed using two-way anova test, considering the randomized blocks design (P < 0.05). RESULTS: The percentage of unprepared canal area was significantly lower in TradAC groups when compared to UltraAC groups (P < 0.05), regardless of the instrument used. The UltraAC/XP group had significantly lower percentage of root dentine removed when compared to other groups (P < 0.05). UltraAC/XP and TradAC/XP groups had significantly lower percentages of AHTD than UltraAC/RC and TradAC/RC groups (P < 0.05). Regarding canal transportation, in the MB root canals, the TradAC/XP group had significantly lower values than other groups (P < 0.05). In general, in ML and distal root canals, TradAC/XP and UltraAC/XP groups had significantly lower values of canal transportation when compared to other groups (P < 0.05). Moreover, the UltraAC/RC had the greatest canal transportation values in MB and distal canals. The UltraAC groups had significantly greater percentages of voids and volume of remaining root filling material within the pulp chamber after cleaning procedures than TradAC groups (P < 0.05). There was no difference in the load capacity amongst groups (P < 0.05). CONCLUSION: The UltraAC/XP and UltraAC/RC groups had significantly greater areas of unprepared canal walls, significantly more voids and volume of root filling material remnants within the pulp chamber after canal filling. UltraAC/XP was associated with significantly less root dentine removal and significantly more AHTD whilst TradAC/XP had overall significantly less canal transportation. No differences were observed in the load capacity amongst groups.

[Pharmacological treatment of non-severe hypertension during pregnancy, postpartum and breastfeeding]. / Tratamiento farmacológico de la hipertensión arterial no severa durante el embarazo, el posparto y la lactancia.

Hypertension (HTN) in pregnancy is defined as systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg. Based on the values, it is classified as non-severe (< 160/110 mmHg) and severe (≥ 160/110 mmHg). Before starting treatment in non-severe HTN, white- coat HTN should be ruled out. If outpatient management is possible, pharmacological initiation is suggested with sustained high values, avoiding < 120/80 mmHg. Safe drugs during pregnancy are methyldopa, labetalol, and nifedipine-retard. The use of nifedipine-XL or amlodipine can be considered with a lower level of evidence of safety. Diuretics, atenolol, and other beta-blockers for antihypertensive purposes is not recommended in this period. Renin-angiotensin-aldosterone system inhibitors are strictly contraindicated. In postpartum and breastfeeding, the same therapeutic regimen used during pregnancy can be maintained, trying early withdrawal of methyldopa. During puerperium, amlodipine and enalapril are safe, with minimal excretion in breast milk.

Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: Position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

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.

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.

T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.

Gradual strenuous running regimen predisposes to osteoarthritis due to cartilage cell death and altered levels of glycosaminoglycans.

OBJECTIVE: To investigate the hypothesis that strenuous running is a predisposing factor for osteoarthritis. DESIGN: Wistar rats were divided into two groups: a control group (CG) and a trained group (TG). The TG underwent a strenuous treadmill running training regimen of controlled intensity, exhibiting progressively improvement of fitness over 12 weeks, running at least 55 km during this period and finally performing an ultra-endurance running exercise to exhaustion. After this period, rats from both groups were euthanized and their knees removed. The articular cartilage was dissected and submitted to histomorphometrical, histomorphological, and immunohistochemical analyses evaluating cell death pathway (caspase-3 and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)) and inflammatory cytokines [interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α)]. In addition, the tissues were analyzed regarding the types and the content of glycosaminoglycans. RESULTS: The TG knee joints exhibited increase in the number of chondrocytes and chondrocyte clusters, as well as significantly increased levels of caspase-3, a protein involved in apoptosis, and of inflammatory cytokines IL-1α and TNF-α. In addition, histologically higher grades of osteoarthritis (Osteoarthritis Research Society International - OARSI grading), and significantly decreased levels of chondroitin sulfate and hyaluronic acid. Knee cartilage thickness and TUNEL did not significantly differ between the two groups. CONCLUSIONS: The articular cartilage of rats subjected to a strenuous running regimen of controlled intensity exhibited molecular and histological characteristics that are present in osteoarthritis.

Structural, microstructural and magnetic properties of (La(1-x)Ca(x))MnO3 nanoparticles.

The crystal and magnetic structures of 10 and 20 nm sized (La1-xCax)MnO3 (x = 0.37, 0.50, 0.75) have been investigated between 5 and 300 K by means of Rietveld refinement of neutron powder diffraction data, coupled with transmission electron microscope observation and magnetization measurements. TEM observation reveals that nanoparticles are strongly affected by strain fields, probably originating from surface pressure. Irrespective of the composition, charge and orbital orderings are suppressed and Fz and Cy spin orderings coexist at low temperature; Cy and Fz orderings likely occur within the strained regions of the nanoparticles and in the matrix respectively. Moreover Gz and Az orderings are sometimes observed, and are likely to be taking place at the border of the strained regions.

Active vaccination with ankyrin G reduces ß-amyloid pathology in APP transgenic mice.

Serum antibodies against amyloid-ß peptide (Aß) in humans with or without diagnosis of Alzheimer's disease (AD) indicate the possibility of immune responses against brain antigens. In an unbiased screening for antibodies directed against brain proteins, we found in AD patients high serum levels of antibodies against the neuronal cytoskeletal protein ankyrin G (ankG); these correlated with slower rates of cognitive decline. Neuronal expression of ankG was higher in AD brains than in nondemented age-matched healthy control subjects. AnkG was present in exosomal vesicles, and it accumulated in ß-amyloid plaques. Active immunization with ankG of arcAß transgenic mice reduced brain ß-amyloid pathology and increased brain levels of soluble Aß(42). AnkG immunization induced a reduction in ß-amyloid pathology, also in Swedish transgenic mice(.) Anti-ankG monoclonal antibodies reduced Aß-induced loss of dendritic spines in hippocampal ArcAß organotypic cultures. Together, these data established a role for ankG in the human adaptive immune response against resident brain proteins, and they show that ankG immunization reduces brain ß-amyloid and its related neuropathology.

Early-onset absence epilepsy: SLC2A1 gene analysis and treatment evolution.

BACKGROUND AND PURPOSES: To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). METHODS: We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. RESULTS: Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3 years after enrollment, use of AEDs at 3 years, failed withdrawals at 3 years, terminal remission of EOAE at 3 years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P = 0.008). CONCLUSIONS: We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED.

M2 muscarinic receptors inhibit cell proliferation in human glioblastoma cell lines.

AIMS: In the present work we investigated the expression of M2 muscarinic receptor subtype in two glioblastoma cell lines and its role in the control of cell proliferation. MAIN METHODS: The M2 receptor transcript and protein expression was studied using RT-PCR and western blot analysis. (3)[H]-thymidine incorporation was used to evaluate cell proliferation in the presence or in the absence of M(2) agonist arecaidine. KEY FINDINGS: We demonstrated that M(2) receptor is expressed in both cell lines, although U251 cells show a higher expression level, compared to U87 cells. The activation of M(2) receptors by the agonist arecaidine decreases cell growth in a dose and time dependent manner. The anti-proliferative effect of arecaidine is also confirmed by the significant decrease of (3)[H]-thymidine incorporation in both cell lines. Moreover the M2 antagonist gallamine counteracts the arecaidine effects confirming M2 receptor involvement in glioma cell growth inhibition. SIGNIFICANCE: These data suggest a role for M2 receptors in the inhibition of glioma cell proliferation and the possibility of exploiting these receptors as new promising tools for glioblastoma therapy.

Errors in ozone risk assessment using standard conditions for converting ozone concentrations obtained by passive samplers in mountain regions.

Passive samplers are often employed to measure ozone concentrations in remote areas such as mountain forests. The potential ozone risk for vegetation is then assessed by calculating the AOT40 exposure index (accumulated hourly ozone concentration exceedances above 40 ppb, i.e. AOT40 = Σ([O(3)] - 40)Δt for any hourly ozone concentration [O(3)] > 40 ppb). AOT40 is customary calculated on the basis of ozone concentrations expressed as a volumetric mixing ratio, while lab sheets normally report ozone concentrations from passive samplers in mass units per cubic metre. Concentrations are usually converted from mass units to ppb using a standard conversion factor taking SATP (Standard Ambient Temperature and Pressure) conditions into account. These conditions, however, can vary considerably with elevation. As a consequence, the blanket application of a standard conversion factor may lead to substantial errors in reporting and mapping ozone concentrations and therefore in assessing potential ozone risk in mountain regions. In this paper we carry out a sensitivity analysis of the effects of uncertainties in estimations of air temperature (T) and atmospheric pressure (P) on the concentration conversion factor, and present two examples from two monitoring and mapping exercises carried out in the Italian Alps. We derived P and T at each site from adiabatic lapse rates for temperature and pressure and analysed the magnitude of error in concentration estimations. Results show that the concentration conversion is much more sensitive to uncertainties in P gradient estimation than to air temperature errors. The concentration conversion factor (cf) deviates 5% from the standard transformation at an elevation of 500 m asl. As a consequence, the standard estimated AOT40 at this elevation is about 13% less than the actual value. AOT40 was found to be underestimated by an average between 25% and 34% at typical elevations of mountain forest stands in the Italian Alps when a correct conversion factor for transforming ozone concentrations from µg m(-3) to ppb is not applied.