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The article presents the author's comments on the origin of the ideas and the solutions to the questions related to the origin of ideas by Buddhist philosopher Nagarjuna, a devoted follower of Gautama Buddha. The author discusses the interpretation of Nagarjuna's philosophy as anti-metaphysical realism and his version of the canonical doctrine of the dependent co-arising.

Background: Tuberous breast deformity is a congenital anomaly affecting young women. Several surgical techniques have been developed, but in many cases, they have not led to the expected results or have led to significant complications. The purpose of our study is to evaluate the efficacy of treating tuberous breast deformity with an innovative 'star-like' incision technique. Methods: Between 2009 and 2013, 25 patients with a tuberous breast deformity underwent surgery at our department. All patients were managed with a star-like incision of the gland and the placement of a subfascial silicone gel implant in a single-stage surgical procedure. An areolar reduction was also performed. Results: Our results, with a maximum follow-up of 4 years, were satisfying. There were no surgical or later complications. The new breasts had a natural shape, correct symmetry, a normal-sized areola, reduced evidence of the 'double-bubble" deformity, good mammary projection, and resolved ptosis. Conclusion: Advantages of the star-like incision technique include lower breast pole restructuring in the volume, length, and shape, suitable breast implant coverage, and proper correction of areola size and herniation. The technique is safe and achieves satisfactory, long-lasting results. Level of Evidence: Level IV, descriptive study [ABSTRACT FROM AUTHOR]

Purpose:Breast augmentation combined with mastopexy is associated with a significantly higher complication rate than augmentation alone. The combination of mastopexy and breast implants has revealed a moderate recurrence of breast ptosis in many patients particularly with use of medium to large implants. Ptosis is the “bottoming out” of the breast tissue with loss of the desired roundness, due to the ptosis of the breast implant and the mammary tissue. In this study, we hypothesize the need for careful planning and careful preoperative surgical execution to minimize this complication.Patients and Methods:Between January 2007 and July 2011, augmentation mastopexy with implant and autologous tissue (“double implant”) was performed for 25 patients with grade III mammary ptosis. All patients underwent inverted-T mastopexy with supramuscular moderately cohesive gel breast implant using an inferior-based flap of de-epitelialized dermoglandular tissue and a superior-based nipple-areola complex pedicle.Results:An inferior-based flap of deepithelialized dermoglandular tissue was used to stabilize the implant and is projection. Breast lifting was performed through a strong anchorage to fascia and to muscle of second intercostal space, improving the profile of the breast. Results were analyzed, no breast ptosis recurrence was noted at 30-month follow-up.Conclusions:Our technique presents the challenge of determining the amount of excess skin to be removed after implantation to create symmetry and provide for skin tightening without compromising tissue vascularization. [ABSTRACT FROM AUTHOR]

Pseudoneglect phenomenon refers to a condition in which healthy subjects tend to perceive the left side of exactly bisected lines as being slightly longer than the right one. However, behavioural data showed that athletes practising an open-skill sport display less pseudoneglect than the general population. Given the fact that so-called exergames (also known as active video games) are platforms designed to fully mimic sport activity, this work intends to investigate whether and how a one-week training period of exergame open-skill sport can determine a similar decrease in pseudoneglect. Fifteen healthy participants (non-athletes) responded to a visuospatial attention task and a control memory task in basal conditions (t0: Pre-game) and after a short period (one week, one hour/day) of tennis exergaming (t1: Post-game). In the Post-game condition, subjects from this experimental group (ExerGame group: EG) reduced leftward space overestimation and made significantly fewer leftward errors compared to the Pre-game condition. Additionally, two other experimental groups were employed: one evaluated within the same conditions of the main experiment but using a non-exergame (Non-Exergame groups: NEG) and the other one without any video game stimulus (Sedentary group: SE). Our findings suggest that daily training of a tennis exergame seems to be able to improve visuospatial attention isotropy by reducing leftward space overestimation, whereas outcomes from non-exergaming and sedentary activity do not modify subjects' performance. [ABSTRACT FROM AUTHOR]

Highlights: [•] Different doses of DMSO are tested in 3 groups of rats after 5 stable epileptic discharges in the DG. [•] 100% and 50% solutions of DMSO with a dose dependent effect reduce the epileptic activity. [•] We infer that DMSO dampens excitotoxic phenomena reducing the glutamatergic transmission. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous molecule acting as a messenger in both the peripheral and the central nervous systems. NO affects synaptic activity by modulating neurotransmitter release and/or receptor function. We previously observed that NO-active compounds modify the bioelectric activity of basal ganglia (BG) units. In this study, we applied microiontophoresis to extracellular in vivo recordings to investigate the effect of NO-active compounds on GABA-evoked responses in the globus pallidus (GP) of anesthetized rats. The changes induced by NO-active drugs on the GABA-induced inhibition were used as indicators of NO modulation. The response to GABA release was tested on recorded GP neurons before and during the administration of S-nitroso-glutathione (SNOG, a NO donor) and/or Nω-nitro- l-arginine methyl ester ( l-NAME), an inhibitor of nitric oxide synthase (NOS); furthermore, SNOG and l-NAME were tested at different ejection currents in order to highlight the possibility of a current-dependent effect in the nitrergic modulation of GABA transmission. In general, during SNOG ejection the magnitude of GABA-evoked responses was reduced, whereas the administration of l-NAME produced the opposite effect. The results suggest that NO-active drugs modulate the response of GP neurons to GABA transmission; the effects induced by SNOG and l-NAME were strictly related to the ejection currents. Then, the modulation of GABAergic transmission by NO could represent a mechanism to finely regulate the GP neurons activity with important consequences on the overall BG function. [ABSTRACT FROM AUTHOR]

Abstract: The anticonvulsant effect of cannabinoids (CB) has been shown to be mediated by the activation of the CB1 receptor. This study evaluates the anticonvulsant activity of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN55,212-2, CB agonist) alone or preceded by the administration of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, selective CB1 antagonist) in an experimental in vivo model of complex partial seizures (maximal dentate gyrus activation – MDA) in the rat. WIN55,212-2 (21mgkg−1) exerted an anticonvulsant effect, significantly reduced by the pre-treatment with AM251 (1mgkg−1, 30min interval). Surprisingly, AM251, administered alone at the same dose, failed to induce any modification in MDA responses. Our data suggest the involvement of the CB system in the inhibitory control of hyperexcitability phenomena in a model of acute partial epilepsy. Although the MDA model per se does not induce a basal activation of CB1 receptors, as suggested by the lack of efficacy of AM251 when administered alone, the partial suppression of WIN55,212-2-induced effects in rats pre-treated with AM251 allows to hypothesise that the WIN55,212-2-induced antiepileptic effect is strictly linked to an increased CB1 receptor activation or to the involvement of further receptor subtypes. [Copyright &y& Elsevier]

The nitric oxide (NO)-active drugs influence on the bioelectric activity of neurons of the pars reticulata of the substantia nigra was studied in urethane-anesthetized rats. A first group of animals was treated with 7-nitro-indazole (7-NI), a preferential inhibitor of neuronal NO synthase. In a second group of rats, electrophysiological recordings were coupled with microiontophoretic administration of Nω-nitro- l-arginine methyl ester ( l-NAME, a NO synthase inhibitor), 3-morpholino-sydnonimin-hydrocloride (SIN-1, a NO donor) and 8-Br-cGMP (a cell-permeable analogue of cGMP, the main second-messenger of NO neurotransmission). 7-NI and l-NAME caused a statistically significant decrease in the firing rate of most of the responsive cells, while application of SIN-1 and 8-Br-CGMP induced statistically significant excitatory effects. The results suggest a NO mediated excitatory modulation of the SNr neurons activity with a possible involvement of the cGMP pathway. [ABSTRACT FROM AUTHOR]

We evaluated the possible additive effect induced by the administration of the anticonvulsant vigabatrin (VGB) and cholecystokinin-8 sulfate (CCK-8S) on an experimental model of partial complex seizures (maximal dentate gyrus activation, MDA). Moreover, the functional involvement of γ-aminobutyric acid (GABA) neurotransmission was tested by iontophoretically administering bicuculline (GABA receptor antagonist) in the dentate gyrus. Urethane anesthetized rats were pretreated with VGB (50, 100 or 200 mg/kg, i.p.) or CCK-8S (8 nmol/kg, i.p.) alone or coadministered with VGB (50 mg/kg, i.p.). Dentate gyrus epileptic activity was obtained through the repetitive electrical stimulation of the angular bundle. MDA latency, duration, and poststimulus afterdischarge (AD) duration were evaluated. The extracellular activity of some dentate neurons was recorded before and during bicuculline iontophoresis. Only the higher dose of VGB reduced the mean duration of dentate MDA and AD. CCK-8S significantly decreased the number of animals exhibiting MDA responses, characterized by increased latency and shorter duration. The coadministration of CCK-8S and VGB (50 mg/kg) significantly increased the anticonvulsant effects, either reducing the number of responding animals or decreasing both MDA and AD durations. During bicuculline iontophoresis, all the modifications induced on the MDA-related activity of dentate neurons by the pretreatments (VGB and/or CCK-8S) were abolished. The results indicate that CCK-8S significantly enhances the VGB-induced anticonvulsant effect in the MDA model of partial epilepsy, probably through an increase of GABA cerebral levels. Such increased anticonvulsant effect becomes evident by using VGB at a lower dose. [ABSTRACT FROM AUTHOR]

Background: The effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of NO synthesis Larginine, alone or in combination, on an experimental model of partial complex seizures (maximal dentate gyrus activation) were studied in urethane anaesthetized rats. The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle and maximal dentate gyrus activation latency, duration and post-stimulus afterdischarge duration were evaluated. Results: Either Lamotrigine (10 mg kg-1) or 7-nitroindazole (75 mg kg-1) i.p. administration had an anticonvulsant effect, significantly reducing the number of animals responding to angular bundle stimulation. On the contrary, i.p. injection of L-arginine (1 g kg-1) induced an aggravation of the epileptiform phenomena, demonstrated by the significant augmentation of the duration of both maximal dentate activation and afterdischarge. Furthermore, the injection of lamotrigine and 7-nitroindazole in combination significantly increased the anticonvulsant effects induced by the same drugs separately, either reducing the number of responding animals or decreasing both maximal dentate gyrus activation and afterdischarge durations. On the contrary, the combined treatment with L-arginine and lamotrigine did not modify the maximal dentate gyrus activation parameters suggesting an adversative effect of L-arginine-increased nitric oxide levels on the lamotrigineinduced anticonvulsant action. Conclusion: The present results indicate that the nitrergic neurotransmission exerts a significant modulatory role in the control of the development of paroxystic phenomena in the maximal dentate gyrus activation model of epilepsy. Finally, our data suggest a functional relationship between the nitric oxide system and the anticonvulsant effect of lamotrigine which could be enhanced by reducing nitric oxide levels and, conversely, dampened by an increased nitrergic activity. [ABSTRACT FROM AUTHOR]

Abstract: The effects induced on the discharge of subthalamic spontaneously active neurons by inhibiting the enzyme nitric oxide synthase was studied in two groups of urethane-anesthetized rats. In the first group of animals (n =10), the activity of subthalamic single units was recorded before and after the systemic administration of 7-nitro-indazole (7-NI, 50mg/kg i.p.), a selective inhibitor of neuronal nitric oxide synthase. In the second group of rats (n =15), Nω-nitro-l-arginine methyl ester (L-NAME), another inhibitor of nitric oxide synthase, was iontophoretically administered while performing single unit extracellular recordings. The activity of most tested spontaneously discharging neurons (8/10) was influenced by 7-NI administration, which always caused a statistically significant decrease in the firing rate of the responsive cells. In contrast, the iontophoretic administration of L-NAME, although influencing many cells (24/32), did not have univocal effects: in fact, 18 cells were inhibited while 6 neurons were excited in a statistically significant manner. We hypothesize that nitric oxide neurotransmission could exert a tonic modulatory influence upon spontaneously discharging subthalamic neurons, with a prevalent excitatory effect. [Copyright &y& Elsevier]

We have chosen to study the effects of both nitric oxide (NO) and cholecystokinin neuromodulatory systems in some motor structures that are frequently involved in excitotoxic phenomena. In particular, 7-nitroindazole, a selective inhibitor of neuronal NO synthase, was administered in control and sulfated cholecystokinin octapeptide-treated rats. Cortical surface, striatal and pallidal depth bioelectric activities were examined through Fast Fourier Transform analysis. Cortical and pallidal recordings revealed an increase of rapid standard rhythms after the inhibition of neuronal NO synthase; in contrast, striatal depth recordings showed a marked increase of slow standard rhythms. All these effects were completely abolished by chronic pre-treatment with sulfated cholecystokinin octapeptide. The results suggest a functional co-operation between cholecystokinin and NO systems in the modulation of the bioelectric activity of all the motor structures examined, and the possibility of preventing excitotoxic damages induced by an anomalous balance between excitatory and inhibitory neurotransmitters in these areas. [Copyright &y& Elsevier]

Single units were recorded in the striatum and in the globus pallidus (GP) of urethane-anesthetized rats under microiontophoretic administration of either Nω-nitro-l-arginine methyl ester (l-NAME, inhibitor of nitric oxide synthase), or 3-morpholino-sydnonimin-hydrocloride (SIN-1, nitric oxide, NO donor). A steady baseline firing of sporadically discharging striatal neurons (basal firing rate <0.1 spikes/s) was evoked by a pulsed microiontophoretic ejection of glutamate. On striatal neurons, microiontophoretic application of SIN-1 induced a current-dependent inhibition (11/13), whereas l-NAME administration produced a clear excitation (9/9). On GP cells, the administration of SIN-1 had excitatory effects (10/15), whereas the administration of l-NAME reduced the neuronal activity (6/6). We hypothesize that NO could exert an intrinsic regulatory action on the activity of both striatal and GP cells. [Copyright &y& Elsevier]

The activity of single units in the striatum of urethane-anesthetized rats was recorded before and after the systemic administration of 7-nitro-indazole (7-NI; 50 mg/kg intraperitoneally), a selective inhibitor of neuronal nitric oxide (NO) synthase. Two neuronal types were clearly distinguishable electrophysiologically, on the basis of either discharge frequency pattern or features of the individual spike waveform (spike duration, negative phase/total duration ratio, and negative phase/total amplitude ratio). Only sporadically discharging neurons (basal firing rate, <0.1 spikes/s) were influenced by 7-NI, which caused a statistically significant increase in their firing rate. In contrast, the activity of continuously discharging neurons (basal firing rate, 4–6 spikes/s) was not affected. We hypothesize that NO neurotransmission could exert a tonic inhibitory influence upon sporadically discharging striatal neurons, which are presumably striatal output neurons. [Copyright &y& Elsevier]

Introduction: Although echinocandins are recommended as first‐line prophylaxis for high‐risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough‐invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. Materials and methods: Two authors independently searched PubMed‐MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS‐I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). Results: 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24–2.99) and observational studies (OR 1.43, 95% CI 0.28–7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97–24.03) was noted. Conclusions: Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted. [ABSTRACT FROM AUTHOR]

Cells and extracts derived from adipose tissue are gaining increasing attention not only in plastic surgery and for aesthetic purposes but also in regenerative medicine. The ability of hyaluronan (HA) to support human adipose stromal cell (hASC) viability and differentiation has been investigated. However, the compatibility of adipose tissue with HA-based formulation in terms of biophysical and rheological properties has not been fully addressed, although it is a key feature for tissue integration and in vivo performance. In this study, the biophysical and biochemical properties of highly concentrated (45 mg/mL) high/low-molecular-weight HA hybrid cooperative complex were assessed with a further focus on the potential application in adipose tissue augmentation/regeneration. Specifically, HA hybrid complex rheological behavior was observed in combination with different adipose tissue ratios, and hyaluronidase-catalyzed degradation was compared to that of a high-molecular-weight HA (HHA). Moreover, the HA hybrid complex's ability to induce in vitro hASCs differentiation towards adipose phenotype was evaluated in comparison to HHA, performing Oil Red O staining and analyzing gene/protein expression of PPAR-γ, adiponectin, and leptin. Both treatments supported hASCs differentiation, with the HA hybrid complex showing better results. These outcomes may open new frontiers in regenerative medicine, supporting the injection of highly concentrated hybrid formulations in fat compartments, eventually enhancing residing staminal cell differentiation and improving cell/growth factor persistence towards tissue regeneration districts. [ABSTRACT FROM AUTHOR]

Several questions emerged from a Virtual Symposium that took place in August 2020 with practitioners and scholars of Buddhism, some of them Buddhist translators from different languages (Chinese, Japanese, Tibetan and Sanskrit) into Portuguese. The motivation of this meeting was to discuss important questions about Buddhism in our day and age, its opportunities and challenges. Throughout the debate it became evident that there is a great cultural gap between Brazil and Asian countries. It also reveals the sophistication and rigor required for translations, as well as the need and difficulty of establishing this debate in academia. This article presents the most important points of each speech, puts them in perspective and makes final considerations about the challenges and opportunities present in the broad topic of translations and academic dialogue with Buddhism. [ABSTRACT FROM AUTHOR]

• BL/BLI combination was the most common antibiotic regimen used for Enterobacteriaceae bloodstream infection (E-BSI). • All-cause 30-day mortality rate was low (6.8%) in patients receiving appropriate empirical/definitive BL/BLI therapy. • Non-susceptibility to ESCs was not associated with increased 30-day mortality or higher 90-day relapse rate. • In multivariate analysis, the only predictor of relapse was immunosuppression, mainly in patients with higher SOFA score. The aim of this study was to investigate risk factors for treatment failure in patients receiving in vitro-active therapy with β-lactam/β-lactamase inhibitor (BL/BLI) for Enterobacteriaceae bloodstream infection (E-BSI). This was a retrospective, single-centre study of patients diagnosed with E-BSI at an Italian centre over a 4-year period. Exclusion criteria were age <18 years, clinical data unavailable, polymicrobial BSI, failure to receive in vitro-active therapy and death within 72 h from drawing the index blood culture. Patients who received BL/BLI as appropriate empirical and/or definitive therapy for ≥50% of the total treatment duration were selected. The primary endpoint was all-cause 30-day mortality. The secondary endpoint was 90-day relapse. Of 1319 eligible patients, 835 were selected. A total of 714 received BL/BLI as appropriate empirical therapy, of whom 522 remained on BL/BLI as definitive therapy and 192 shifted to another antibiotic for <50% of the treatment duration; 121 received BL/BLI as definitive therapy only. Non-susceptibility to extended-spectrum cephalosporins (NS-ESCs) was detected in 207 episodes (24.8%). All-cause 30-day mortality was 6.8%. In multivariate analysis adjusted for NS-ESC, independent predictors of mortality were Charlson comorbidity index, septic shock, Proteus spp. and CVC-related BSI, whilst urinary source was a protective factor. The 90-day relapse rate was 4.2%. Immunosuppression was the main independent predictor for relapse. BL/BLI was the most common antibiotic administered to patients with E-BSI in this cohort. Among patients appropriately treated with BL/BLI, failure rates were low and were primarily associated with underlying diseases, clinical severity at BSI onset and infection source. [ABSTRACT FROM AUTHOR]

Background Nipple-areolar complex (NAC) reconstruction is the final stage of breast reconstruction. Ideal reconstruction of the NAC requires symmetry in position, size, shape, texture, pigmentation, and permanent projection, and although many technical descriptions of NAC reconstruction exist in the medical literature, there is no gold standard technique. The technique devised by the authors is very versatile, with excellent results, and it enables 1-step reconstruction with optimal results in terms of shape and nipple projection. Methods Our technique consists of a combination of modified local flaps and a full-thickness skin graft. Patients were observed for 18 months to estimate the amount of retraction. This procedure was performed in 40 patients, four of them bilaterally. The duration of the follow- up was 30 months. Complications occurred in 10% of patients, and included infections (5%), ischemia (2.5%), and hematoma (2.5%). Results No cases of total nipple necrosis were reported. The NAC shape remained optimal in all cases, with a very small reduction of the vertical and horizontal diameters of the areola, which maintained its designed round shape well, and negligible retraction in the diameter and projection of the nipple. Conclusions The oval technique represents a major step forward, involving a combination of existing techniques, such as the C-V flap and the cutaneous graft, to achieve excellent results regarding areola shape and nipple projection, significantly reducing the cases of nipple ischemia. These results were substantially obtained through subcutaneous equatorial sutures, skin grafting, and flattening of the apexes of the flap. [ABSTRACT FROM AUTHOR]

Highlights • A validated method to collect and analyze the fuel released during flammability test. • This method is useful to study flame retardancy mechanism in real flaming conditions. • Blowing-out mechanism in flame retarded epoxy resin was elucidated by this method. • DOPO-POSS in epoxy significantly changes composition of fuel mix feeding the flame. • Lower flammability of blown-out fuel explained by the high phenol/hydrocarbon ratio. Abstract A novel method was developed for the sampling of volatiles produced by polymer decomposition during UL-94 standard flammability tests, allowing collecting, separating and analyzing the precise composition of the fuel mixture feeding the flame in the real flaming conditions. The system was validated on epoxy resin/Polyhedral Oligomeric SilSesquioxanes (POSS) and found extremely informative for the understanding of the flame retardancy mechanisms previously referred to as the "blowing-out effect". Collected products were analyzed by infrared spectroscopy and gas chromatography/mass spectroscopy, to identify the gaseous and liquid decomposition products, allowing depicting a comprehensive decomposition pathway for the epoxy resin. Lightweight volatiles, gaseous at room temperature, showed limited differences as a function of DOPO-POSS (polyhedral oligomeric silsesquioxane functionalized with 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide), whereas mixtures of liquid products evidenced for dramatic changes in the relative concentration as a function of DOPO-POSS. In pristine epoxy resin, the most abundant products were recognized as benzene, phenol, naphthalene and toluene, along with several tens of other aromatic products observed in lower amounts. The presence of DOPO-POSS at low concentration (2.5%) radically changes the composition of the aromatic volatiles mixture, as no significant amount of benzene is produced, while phenol becomes the main product, accounting for about half of the total, isopropyl phenol and bisphenol A, along with several tens of other products in lower concentrations. Such modification of the fuel mixture feeding the flame provided an explanation for the lower flammability of this formulation, as well as for the phenomenology of the blowing out effect. [ABSTRACT FROM AUTHOR]

• Pre-menopausal women with lowest breast fat-density (fatty breast) vs. higher breast fat-density (non-fatty breast) are high-risk population for cardiovascular diseases and worse prognosis. • The worse cardiovascular prognosis could be due to expression in the breast fat tissue in fatty vs. non-fatty pre-menopausal women of sodium glucose transporter 2 (SGLT2), inflammatory cytokines and sirtuins. • Indeed, these molecular effectors could condition the intima-media wall thickness (IMT), left ventricle mass (LVM), left ventricle ejection fraction (LVEF), and myocardial performance index (MPI), and its normalization. • The fatty vs. non-fatty breast women over-expressed SGLT2/inflammatory cytokines, and down-regulated breast sirtuins. • SGLT2/inflammatory cytokines expression and inversely the tSIRT3 and breast percentage density linked to ΔMPI at 1 year of follow-up. • Fatty breast and SGLT2 inversely predicted the normalization of cardiac performance (NCP). • SIRT-3 increased the probability of NCP at 1 year of follow-up. To evaluate the expression of sodium-glucose transporter 2 (SGLT2), inflammatory cytokines, and sirtuins in breast fat tissue at baseline, and serum cytokines of fatty vs. non-fatty pre-menopausal women at baseline, and at 12 months of follow-up. To correlate SGLT2/cytokines/sirtuins expression to clinical variables, and their changes (Δ) at follow-up, as intima-media wall thickness (IMT), left ventricle mass (LVM), left ventricle ejection fraction (LVEF), and myocardial performance index (MPI), and its normalization. Pre-menopausal women with the lowest breast fat density (fatty breast) vs. higher breast fat density (non-fatty breast) are a high-risk population for cardiovascular diseases and worse prognosis. We analyzed SGLT2/cytokines/sirtuins of excised fatty breasts of fatty vs. non-fatty pre-menopausal women. We correlated SGLT2/cytokines/sirtuins to Δ IMT, Δ LVM, Δ LVEF, and Δ MPI, and normal cardiac performance (NCP) at 1 year of follow-up. fatty vs. non-fatty breast over-expressed SGLT2/inflammatory cytokines, with lowest values of sirtuins (p <0.05). We found a direct correlation between SGLT2 (R2 0.745), TNFα (R2 0.262), and ΔMPI (p <0.05), and an inverse correlation between breast density (R2 -0.198), SIRT-3 (R2–0.181), and ΔMPI (p <0.05). Fatty breast (0.761, CI 95% [0.101–0.915]), SGLT2 (0.812, CI 95% [0.674–0.978]) and SIRT-3 (1.945, CI 95% [1.201–3.148]) predicted NCP at 1 year of follow-up. fatty vs. non-fatty breast women over-expressed SGLT2/inflammatory cytokines, and down-regulated breast sirtuins. SGLT2/inflammatory cytokines expression and inversely the tissue sirtuin 3 (tSIRT3) and breast percentage density linked to ΔMPI at 1 year of follow-up. Fatty breast and SGLT2 inversely predicted NCP; SIRT-3 increased the probability of NCP at 1 year of follow-up. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Management of infections due to carbapenemase‐resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT‐SOT‐CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking. Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7‐year period. Primary endpoint was all‐cause 30‐day mortality from infection onset. A comparison between INCREMENT‐SOT‐CPE and other selected scores was performed. A two‐level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut‐point were calculated. Multivariable Cox regression analysis of risk factors for all‐cause 30‐day mortality was carried out. Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46–62) and 157 were males (62.8%). All‐cause 30‐day mortality was 35.6%. A sequential organ failure assessment (SOFA) score ≥ 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT‐SOT‐CPE ≥ 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT‐SOT‐CPE score ≥ 11 and SOFA score ≥ 11 were independently associated with all‐cause 30‐day mortality, while a tigecycline‐based targeted regimen was found to be protective. Conclusions: Both INCREMENT‐SOT‐CPE ≥ 11 and SOFA ≥ 11 were identified as strong predictors of all‐cause 30‐day mortality in a large cohort of CRE carriers developing infection after LT. [ABSTRACT FROM AUTHOR]

Oral candidiasis (OC) is an opportunistic fungal infection of the oral mucosae, sustained by Candida albicans or other non-albican Candida species (NAC), usually eradicated by conventional antifungals of the classes of azoles, polyenes, or derivative from echinocandins. OC usually occurs under predisposing local or systemic factors. C. lusitaniae is an opportunistic strain that is rarely responsible for human infection and occurs mainly in severe immunocompromised states. The present work reported an unconventional case of OC in an otherwise healthy immunocompetent woman sustained by C. lusitaniae and a multi-resistant strain of C. albicans. [ABSTRACT FROM AUTHOR]

The mouse excisional dorsal full-thickness wound model with a silicon splint fixed on the skin has been widely used to mimic human wound healing. However, the method cannot accurately quantify dermal remodeling, since the initial point of epithelialization on the wound surface is unclear. To overcome this limitation, we have developed a novel mouse excisional wound model to assess the degree of epithelial extension and regeneration, using a plastic ring-shaped splint fixed beneath the surrounding epidermal tissue. At the end of the experiment, tissue samples were fixed in formalin, the splint was excised, and paraffin sections were prepared. Splint holes, corresponding to the prior location of the splint, were evident on the tissue cross-sections, and the epidermis above the holes was considered the initial excision site. The epidermal contraction and epithelial regeneration, as independent essential tissue alterations in wound healing, could be distinguishable and quantified. Compared with previous splint models, this method provides an accurate evaluation of epidermal processes in wound healing, and can be a platform to assess the effects of various wound healing factors. J. Cell. Physiol. 232: 1225-1232, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Guanosine (GUO), widely considered a key signaling mediator, is implicated in the regulation of several cellular processes. While its interaction with neural membranes has been described, GUO still is an orphan neuromodulator. It has been postulated that GUO may eventually interact with potassium channels and adenosine (ADO) receptors (ARs), both particularly important for the control of cellular excitability. Accordingly, here, we investigated the effects of GUO on the bioelectric activity of human neuroblastoma SH-SY5Y cells by whole-cell patch-clamp recordings. We first explored the contribution of voltage-dependent K+ channels and, besides this, the role of ARs in the regulation of GUO-dependent cellular electrophysiology. Our data support that GUO is able to specifically modulate K+-dependent outward currents over cell membranes. Importantly, administering ADO along with GUO potentiates its effects. Overall, these results suggested that K+ outward membrane channels may be targeted by GUO with an implication of ADO receptors in SH-SY5Y cells, but also support the hypothesis of a functional interaction of the two ligands. The present research runs through the leitmotif of the deorphanization of GUO, adding insight on the interplay with adenosinergic signaling and suggesting GUO as a powerful modulator of SH-SY5Y excitability. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a fascinating signalling molecule implicated in a plethora of biological functions, especially at the synaptic level. Exploring neurotransmission in the hippocampus could be instrumental in the individuation of putative targets for nitric-oxide mediated neuromodulation, especially in terms of the potential repercussions on fundamental processes i.e. synaptic plasticity and excitability-related phenomena. Among these targets, endovanilloid signalling constitutes an object of study since Transient Receptors Vanilloid type 1 (TRPV1) channels possess a NO-sensitive gate modulating its activation. Also, NO has been referred to as a mediator for numerous endocannabinoid effects. Notwithstanding, the linkage between TRPV1 and NO systems in neuromodulation still remains elusive. To this end, we aim at investigating the involvement of TRPV1 in nitric oxide-mediated influence on hippocampal processes. Electrophysiological whole-cell recordings in CA1 pyramidal neurons were applied to evaluate excitatory neurotransmission in rat brain slices. Indeed, miniature excitatory postsynaptic currents (mEPSCs) were analysed upon pharmacological manipulation of TRPV1 and NO signalling pathways. In detail, only the administration of the specific TRPV1 exogenous agonist – capsaicin - reduced the frequency and amplitude of mEPSC similarly to the inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (7NI). In contrast, capsazepine, TRPV1 antagonist, does not influence excitatory transmission. The combined TRPV1 activation and nNOS blockade confirm the presence of a putative common mechanism. When we administered the endovanilloid-endocannabinoid ligand, i.e. anandamide, we unveiled a potentiation of neurotransmission that was selectively reverted by 7NI. Our data suggest that nitric oxide influences TRPV1 hippocampal signalling since these channels are not constitutively active, but can be "on-demand" activated to modulate excitation in CA1 pyramidal neurons, and that this effect is linked to nitric oxide production. [Display omitted] • Nitric oxide production modulates excitatory transmission in CA1 pyramidal neurons. • TRPV1 influence nitrergic modulation of miniature excitatory post-synaptic currents. • Nitrergic intracellular levels are correlated with on-demand TRPV1-CB1 signaling. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25–50–100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome–lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration. [ABSTRACT FROM AUTHOR]

Polycaprolactone nanofibers are used as scaffolds in the field of tissue engineering for tissue regeneration or drug delivery. Polycaprolactone (PCL) is a biodegradable hydrophobic polyester used to obtain implantable nanostructures, which are clinically applicable due to their biological safety. Polydatin (PD), a glycosidic precursor of resveratrol, is known for its antioxidant, antitumor, antiosteoporotic, and bone regeneration activities. We aimed to use the osteogenic capacity of polydatin to create a biomimetic innovative and patented scaffold consisting of PCL-PD for bone tissue engineering. Both osteosarcoma cells (Saos-2) and mesenchymal stem cells (MSCs) were used to test the in vitro cytocompatibility of the PD-PCL scaffold. Reverse-phase (RP) HPLC was used to evaluate the timing release of PD from the PCL-PD nanofibers and the MTT assay, scanning electron microscopy, and alkaline phosphatase (ALP) activity were used to evaluate the proliferation, adhesion, and cellular differentiation in both osteosarcoma and human mesenchymal stem cells (MSCs) seeded on PD-PCL nanofibers. The proliferation of osteosarcoma cells (Saos-2) on the PD-PCL scaffold decreased when compared to cells grown on PLC nanofibers, whereas the proliferation of MSCs was comparable in both PCL and PD-PCL nanofibers. Noteworthy, after 14 days, the ALP activity was higher in both Saos-2 cells and MSCs cultivated on PD-PCL than on empty scaffolds. Moreover, the same cells showed a spindle-shaped morphology after 14 days when grown on PD-PCL as shown by SEM. In conclusion, we provide evidence that nanofibers appropriately coated with PD support the adhesion and promote the osteogenic differentiation of both human osteosarcoma cells and MSCs. [ABSTRACT FROM AUTHOR]

Extensive researches have deepened knowledge on the role of synaptic components in epileptogenesis, but limited attention has been devoted to the potential implication of the cytoskeleton. The study of the development of epilepsy and hyperexcitability states involves molecular, synaptic, and structural alterations of neuronal bioelectric activity. In this paper we aim to explore the neurobiological targets involved in microtubule functioning and cytoskeletal transport, i.e. how dynamic scaffolding of microtubules can influence neuronal morphology and excitability, in order to suggest a potential role for microtubule dynamics in the processes turning a normal neuronal network in a hyperexcited one. Pathophysiological alterations of microtubule dynamics inducing neurodegeneration, network remodeling and relative impairment on synaptic transmission were overviewed. Recent researches were reported on the phosphorylation state of microtubule-associated proteins such as tau in neurodegenerative diseases and epileptic states, but also on the effect of microtubule-active agents influencing cytoskeleton destabilization in epilepsy models. The manipulation of microtubule polymerization was found effective in the modulation of hyperexcitability. In addition, it was considered the importance of microtubules and related neurotrophic factors during neural development since they are essential for the formation of a properly functional neuronal network. Otherwise, this can lead to cognitive deficits, hyperexcitability phenomena and neurodevelopmental disorders. Lastly, we evaluated the role of microtubule dynamics on neuronal efficiency considering their importance in the transport of mitochondria, cellular elements fulfilling energy requirements for neuronal activity, and a putative influence on cannabinoid-mediated neuroprotection. This review provides novel perspectives for the implication of microtubule dynamics in the development of epileptic phenomena. [ABSTRACT FROM AUTHOR]

Backgrounds: Obese pre-diabetics over express cytokines that influence myocardial function via microRNAs (miRs) expression. Objectives: To evaluate inflammatory/oxidative stress, miRs' expression and cardiovascular function in obese pre-diabetics assigned to metformin therapy vs. placebo vs. normo-glycemics at 12 months of follow-up. Materials and methods: Eighty-three obese patients after abdominoplastic surgery were divided in pre-diabetics (n 55), normo-glycemics (n 28), and assigned to hypocaloric diet. Pre-diabetics were assigned to metformin (n 23) or to placebo (n 22) plus hypocaloric diet. Results: Obese pre-diabetics in metformin vs. placebo, and obese pre-diabetics with placebo vs. normoglycemics, had significant differences about IMT, MPI, and LVM (p < 0.05). Obese pre-diabetics in metformin vs. placebo showed significant reduction in serum miR-195 and miR-27 (p < 0.05). Obese pre-diabetics in metformin vs. normoglycemics showed higher expression of serum miR-195 and miR-27 (p < 0.05). Finally, we found inverse relation between IMT and insulin, HOMA-IR, miR-195, miR-27; between LVEF and Insulin, HOMA-IR, miR-195 and miR-27. We found inverse correlation between LVM and sirtuin-1, Insulin, HOMA-IR, miR-195 and miR-27, and direct correlation with interleukin-6. MPI inversely linked to miR-195 and miR-27. Conclusions: In obese pre-diabetics', metformin significantly reduces inflammation/oxidative stress, and miR-195 and miR-27, with reduction in LVM, IMT. [ABSTRACT FROM AUTHOR]

Background: Stretch marks (SM) are nowadays the most common aesthetic pathology of the body; in the XX century, it mainly affected pregnant women, while today it also affects teenagers during puberty, boys and girls without distinction. The aim of this study was to evaluate possible variations in the histological structure of the skin—in terms of quality/quantity of the extracellular matrix and of the collagen and elastic fibers—following the electromagnetic fields and negative pressure (V-EMF) treatment as regards hypotonia and SMs. Materials and Methods: For the current study, 60 women, aged between 25 and 45, were examined. All of them presented deep, white or pearly white colored SMs having had them for between 12 and 25 years. These were documented, asking patients their level of satisfaction, through pictures and biopsies. All patients underwent a cycle of 6 or 8 weekly sessions; everyone was highly satisfied with the results obtained. Results: Biopsies proved that the tissue was reorganized and restored to the original volume, characterized by the production of new, high-quality collagen and elastin molecules, by the reorganization of the basement membrane and by the correct positioning of the melanocytes. No side effects were observed during the treatments. This synergy stands as the most suitable treatment of striae rubra and alba. Conclusion: V-EMF enhances the keratinocyte migration base, melanocytes, and promotes neoangiogenesis with the result of improvement in the SM. [ABSTRACT FROM AUTHOR]

Endocannabinoid system is considered a relevant player in the regulation of neuronal excitability, since it contributes to maintaining the balance of the synaptic ionic milieu. Perturbations to bioelectric conductances have been implicated in the pathophysiological processes leading to hyperexcitability and epileptic seizures. Cannabinoid influence on neurosignalling is exerted on classic receptor-mediated mechanisms or on further molecular targets. Among these, transient receptor potential vanilloid (TRPV) are ionic channels modulated by cannabinoids that are involved in the transduction of a plethora of stimuli and trigger fundamental downstream pathways in the post-synaptic site. In this review, we aim at providing a brief summary of the most recent data about the cross-talk between cannabinoid system and TRPV channels, drawing attention on their role on neuronal hyperexcitability. Then, we aim to unveil a plausible point of interaction between these neural signalling systems taking into consideration nitric oxide, a gaseous molecule inducing profound modifications to neural performances. From this novel perspective, we struggle to propose innovative cellular mechanisms in the regulation of hyperexcitability phenomena, with the goal of exploring plausible CB-related mechanisms underpinning epileptic seizures. [ABSTRACT FROM AUTHOR]

Cannabinoids (CB), transient receptors potential vanilloid type 1 (TRPV1) and nitric oxide (NO) were found to be interlinked in regulating some neuronal functions such as membrane excitability and synaptic transmission. TRPV1 play a fundamental role since it represents a synaptic target for CB that triggers several downstream cellular pathways. In this regard, recent evidence report that TRPV1 could influence NO production by modulating neuronal NO synthase (nNOS) activity. In the present research, we pointed to manipulate nNOS function to assess its role on TRPV1 signalling in hyperexcitability conditions elicited in the dentate gyrus of hippocampal formation. The activation of TRPV1 receptors is achieved by administering capsaicin (CAP), the main TRPV1 agonist exerting a widely reported proepileptic effects. In order to focus on nNOS activity, we used 7-nitroindazole (7NI), nNOS inhibitor, or L-Arginine (ARG), NO precursor, before CAP. Then, the effects of each of these co-administration protocols were tested in presence of WIN 55,212, a CB agonist. The study was conducted in rats using an electrically-induced acute model of temporal lobe hyperexcitability, the Maximal Dentate Activation (MDA), considering different indicators of paroxysmal activity such as: percentage of responses to electrical stimulation, MDA discharge parameters and threshold current intensity for MDA. Data showed that the excitatory effects of CAP were reduced by 7NI and enhanced by ARG pretreatments, respectively. In addition, the co-treatment with WIN counteracted CAP effect, substantially resulting in an inhibitory effect. Finally, the CAP-WIN functional interaction appeared to be modulated by interfering with NO signalling since 7NI increased the inhibitory effect induced by the co-treatment with CAP and WIN, whereas ARG reduced it. These findings suggest that nNOS function could be involved in the CB/TRPV1 signalling and shed light on a new putative cannabinoid-related control of neuronal hyperexcitability in the hippocampus [ABSTRACT FROM AUTHOR]

Autologous fat grafting procedures in plastic surgery have been extensively used to reinforce soft tissue in congenital or acquired tissue impairments. With this background, the aim of this study is firstly to examine the impact of a selective centrifugation on existing adipose stem cells (ASCs) in terms of stemness profile maintenance and, secondly, to investigate the effect of restoring volume in reconstruction on patients affected by soft tissue damage. After centrifugation, the fat graft products were separated into two layers and subsequently examined in vitro for the expression of CD34, CD90, CD117, CD105, CD29, CD31, CD44, CD73, CD133, CD14 and CD45 markers by flow cytometry and gene expression analyses were performed for Sox2, WNT3A, END, CD44, FUT4, COLL1, CTNNB1, hbEGF, KRTLG, MMP2 and VIM genes. The results showed that in the middle-high density (MHD) layer there was a peak concentration of ASCs, compared to another layer obtained after centrifugation. Research carried out on patients under treatment for soft tissue regeneration using cells obtained from MHD layer selection will be fundamental in comparative analysis. These studies will lead to an adequate standardization of outcomes, provided that treatment is performed through cell selection. Therefore, a unique procedure in tissue reconstruction and regeneration through fat grafting is presented here. [ABSTRACT FROM AUTHOR]

Background: The etiology of non-healing ulcers depends on both systemic and local factors. The introduction of advanced dressing, negative wound therapy and compression therapy have undoubtedly improved clinical outcomes. The principal aim of study was to demonstrate the efficacy of dermal micrografts in the treatment of ulcers with different etiologies. The second aim was to investigate in vitro the action of micrografts in the regenerative process. Methods: The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons. Results: We observed in vivo the ability of dermal autologous micrografts to improve the healing of venous, diabetic, pressure and post-traumatic ulcers after few week of treatment accomplished in general with a better quality of life for the patients. In vitro results showed that these micrografts express mesenchymal stem cells (MSCS) marker such as CD34, CD73, CD90 and CD105, and are able to form a viable and proliferative biocomplex with collagen sponge. Finally, the site of ulcers displayed a different expression of epidermal growth factors, insulin-like growth factors, platelet-derived growth factors and their receptors and tumor necrosis factor-β with respect to healthy skin samples. Conclusion: We reported a good outcome for the treatment of chronic ulcers using dermal autologous micrografts. Finally, we suggest that the positivity to MSCs markers and the ability to interact with a scaffold can play a key role in their regenerative properties. [ABSTRACT FROM AUTHOR]

Background Pathological scars occur following injuries and are often considered esthetically unattractive. Several strategies have been attempted to improve these types of scars using both surgical and nonsurgical methods. The most common treatments include cryotherapy, intralesional corticosteroid injections, 5-fluorouracil, bleomycin, interferon, and verapamil. Aims In this study, we aim to investigate the effectiveness of dermal autologous micrografts in the treatment of pathological scars resulting from burns, trauma, or any iatrogenic source. Methods We used a new clinical practice called Rigenera Protocol to obtain autologous micrografts which were in turn injectable in the patients. Results A significant improvement was observed in appearance and texture of the exaggerated scars in all cases following already 4 months of autologous micrograft treatment We have also shown that these micrografts are composed of mesenchymal stem cells and in addition, histological evaluation verified restoration of the structural layers immediately below the epidermis and a horizontal realignment of collagen fibers in the papillary dermis. Conclusion Our results clearly demonstrate the optimal outcomes obtained following treatment with dermal micrografts on exaggerated scars with different etiologies. However, further studies are required to confirm the efficacy of this new technique. [ABSTRACT FROM AUTHOR]

The exogenous cannabinoid agonist WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN), has revealed to play a role on modulating the hyperexcitability phenomena in the hippocampus. Cannabinoid-mediated mechanisms of neuroprotection have recently been found to imply the modulation of transient receptor potential vanilloid 1 (TRPV1), a cationic channel subfamily that regulate synaptic excitation. In our study, we assessed the influence of pharmacological manipulation of TRPV1 function, alone and on WIN antiepileptic activity, in the Maximal Dentate Activation (MDA) acute model of temporal lobe epilepsy. Our results showed that the TRPV1 agonist, capsaicin, increased epileptic outcomes; whilst antagonizing TRPV1 with capsazepine exerts a protective role on paroxysmal discharge. When capsaicin is co-administered with WIN effective dose of 10 mg/kg is able to reduce its antiepileptic strength, especially on the triggering of MDA response. Accordingly, capsazepine at the protective dose of 2 mg/kg managed to potentiate WIN antiepileptic effects, when co-treated. Moreover, WIN subeffective dose of 5 mg/kg was turned into effective when capsazepine comes into play. This evidence suggests that systemic administration of TRPV1-active drugs influences electrically induced epilepsy, with a noticeable protective activity for capsazepine. Furthermore, results from the pharmacological interaction with WIN support an interplay between cannabinoid and TRPV1 signaling that could represent a promising approach for a future pharmacological strategy to challenge hyperexcitability-based diseases. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCAs) may be defined as tumors that derived from the biliary tree with the differentiation in the biliary epithelial cells. This tumor is malignant, extremely aggressive with a poor prognosis. It can be treated surgically and its pathogenesis is poorly understood. The tumor microenvironment (TME) is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis. Besides cancer stem cells (CSCs) can modulate tumor growth, stroma formation, and migratory capability. The initial stage of tumorigenesis is characterized by genetic mutations and epigenetic alterations due to intrinsic factors which lead to the generation of oncogenes thus inducing tumorigenesis. CSCs may result from precancerous stem cells, cell de-differentiation, normal stem cells, or an epithelial-mesenchymal transition (EMT). CSCs have been found in the cancer niche, and EMT may occur early within the tumor microenvironment. Previous studies have demonstrated evidence of cholangiocarcinoma stem cells (CD133, CD24, EpCAM, CD44, and others) and the presence of these markers has been associated with malignant potential. The interaction between TME and cholangiocarcinoma stem cells via signaling mediators may create an environment that accommodates tumor growth, yielding resistance to cytotoxic insults (chemotherarapeutic). While progress has been made in the understanding of the mechanisms, the interactions in the tumorigenic process still remain a major challenge. Our review, addresses recent concepts of TME-CSCs interaction and will emphasize the importance of early detection with the use of novel diagnostic mechanisms such as CCA-CSC biomarkers and the importance of tumor stroma to define new treatments. [ABSTRACT FROM AUTHOR]

The occurrence of sinkholes not directly related to karst has been determined in several areas worldwide in recent years. These phenomena may be particularly dangerous to humans and infrastructure due to their subtle origin and need to be carefully examined. In this work, we describe five sinkholes recently identified in a hilly setting of Southern Italy characterized by Pliocene conglomerate and sand, and variously dislocated by tectonic structures. The sinkholes were examined by different methods (interpretation of multi-temporal aerial photos, geological, geomorphological and geophysical surveys). An historical analysis was performed to collect and critically evaluate information regarding the age of the phenomena. Based on this information, it can be conjectured that two of the five sinkholes developed during the 2000-2001 winter; two of the remaining probably originated during the 70s; the last one opened sometime between February 2001 and November 2007. Based on such chronology, attempts have been performed to identify the likely triggers, through hydrological and seismic analyses. In both cases, no immediate correlation could be found. The origin of the studied phenomena remains uncertain, and may be related to sub-cutaneous erosion, in an area that is renowned to be rich in groundwater. Local changes in the water table, related to climate and/or man-induced activities, may have triggered the development of the cover suffusion-type sinkholes. The present work highlights the potential for this type of phenomena to occur in geological settings without the direct presence of soluble rocks at the surface, a condition quite common in Southern Italy, and the need to carry out further studies in order to better comprehend their mechanisms of origin and successive evolution, and to properly evaluate the related hazard. [ABSTRACT FROM AUTHOR]

Highlights: [•] Pregnenolone sulphate facilitates the acquisition of spatial information. [•] Pregnenolone sulphate enhances simple and complex object discrimination. [•] Pregnenolone sulphate increases hippocampal and perirhinal neuronal firing. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC) therapy holds promise for treating diseases and tissue repair. Regeneration of skeletal muscle tissue that is lost during pathological muscle degeneration or after injuries is sustained by the production of new myofibers. Human Adipose stem cells (ASCs) have been reported to regenerate muscle fibers and reconstitute the pericytic cell pool after myogenic differentiation in vitro. Our aim was to evaluate the differentiation potential of constructs made from a new cross-linked hyaluronic acid (XHA) scaffold on which different sorted subpopulations of ASCs were loaded. Thirty days after engraftment in mice, we found that NG2+ ASCs underwent a complete myogenic differentiation, fabricating a human skeletal muscle tissue, while NG2− ASCs merely formed a human adipose tissue. Myogenic differentiation was confirmed by the expression of MyoD, MF20, laminin, and lamin A/C by immunofluorescence and/or RT-PCR. In contrast, adipose differentiation was confirmed by the expression of adiponectin, Glut-4, and PPAR-γ. Both tissues formed expressed Class I HLA, confirming their human origin and excluding any contamination by murine cells. In conclusion, our study provides novel evidence that NG2+ ASCs loaded on XHA scaffolds are able to fabricate a human skeletal muscle tissue in vivo without the need of a myogenic pre-differentiation step in vitro. We emphasize the translational significance of our findings for human skeletal muscle regeneration. J. Cell. Physiol. 228: 1762-1773, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Of Turin; 3 Biosfered s.r.l., Turin; 4 Department of Molecular Biotechnology and Health Sciences, University of Torino; 5 Abel Nutraceuticals s.r.l., Turin, Italy Hypercholesterolemia is one of the major causes of Cardio-Vascular Diseases, which risk is further increased if other forms of dyslipidemia occur. The present findings may be a useful basis to further focus on the impact of diseases associated to oxidative stress on erythrocytes homeostasis. As cell homeostasis critically depends on the efficiency of membrane transport systems, rising attention has been devoted to the link between oxidative stress, ion transport, and diseases. [Extracted from the article]

Background: Hyaluronans exist in different forms, accordingly with molecular weight and degree of crosslinking. Here, we tested the capability to induce osteogenic differentiation in hDPSCs (human dental pulp stem cells) of three hyaluronans forms: linear pharmaceutical-grade hyaluronans at high and (HHA) low molecular weight (LHA) and hybrid cooperative complexes (HCC), containing both sizes. Methods: hDPSCs were treated with HHA, LHA, HCC for 7, 14 and 21 days. The effects of hyaluronans on osteogenic differentiation were evaluated by qRT-PCR and WB of osteogenic markers and by Alizarin Red S staining. To identify the involved pathway, CD44 was analyzed by immunofluorescence, and YAP/TAZ expression was measured by qRT-PCR. Moreover, YAP/TAZ inhibitor-1 was used, and the loss of function of YAP/TAZ was evaluated by qRT-PCR, WB and immunofluorescence. Results: We showed that all hyaluronans improves osteogenesis. Among these, HCC is the main inducer of osteogenesis, along with overexpression of bone related markers and upregulating CD44. We also found that this biological process is subordinate to the activation of YAP/TAZ pathway. Conclusions: We found that HA's molecular weight can have a relevant impact on HA performance for bone regeneration, and we unveil a new molecular mechanism by which HA acts on stem cells. [ABSTRACT FROM AUTHOR]

Keloids and hypertrophic scars are abnormal responses to wound healing. In general, keloids exhibit a proliferative growth beyond the margins of the scar and remain persistent; while hypertrophic scars are contained to the original wound and may regress over time. In particular, keloid formation is one of the most challenging clinical problems, with increasing frequency in surgical practice. Many treatments are available such as intralesional corticosteroids, topical applications, cryotherapy, surgical excision, radiation therapy, silicone gel sheeting, pressure therapy, and laser therapy. There are no set guidelines for the treatment of keloids and the most common treatments are individualized and depended on the distribution, size, thickness, and consistency of lesions. The authors have evaluated carbon dioxide laser successfully in the treatment of keloids and the aim of this study was to determine the immediate and long-term histologic and clinical effects of keloids after carbon dioxide laser. Fifty consecutive patients (40 females, 10 males, ages 18-60 years, mean age 40 years) with moderate to severe keloids were evaluated. All the patients received regional treatments (deltoid, elbow, chin, and ear) in an outpatient setting with a high-energy pulsed CO2 laser. Significant immediate and prolonged clinical improvement in skin tone, texture, and appearance of carbon dioxide laser was examined in all patients. Dermal remodeling was observed also on histologic examination of biopsied tissue after treatment. Carbon dioxide laser appears to be effective and well tolerated for the treatment of keloids, avoiding the adverse effects and lengthy recovery time. [ABSTRACT FROM AUTHOR]

Keloids and hypertrophic scars are abnormal responses to wound healing. In general, keloids exhibit a proliferative growth beyond the margins of the scar and remain persistent; while hypertrophic scars are contained to the original wound and may regress over time. In particular, keloid formation is one of the most challenging clinical problems, with increasing frequency in surgical practice. Many treatments are available such as intralesional corticosteroids, topical applications, cryotherapy, surgical excision, radiation therapy, silicone gel sheeting, pressure therapy, and laser therapy. There are no set guidelines for the treatment of keloids and the most common treatments are individualized and depended on the distribution, size, thickness, and consistency of lesions. The authors have evaluated carbon dioxide laser successfully in the treatment of keloids and the aim of this study was to determine the immediate and long-term histologic and clinical effects of keloids after carbon dioxide laser. Fifty consecutive patients (40 females, 10 males, ages 18-60 years, mean age 40 years) with moderate to severe keloids were evaluated. All the patients received regional treatments (deltoid, elbow, chin, and ear) in an outpatient setting with a high-energy pulsed CO laser. Significant immediate and prolonged clinical improvement in skin tone, texture, and appearance of carbon dioxide laser was examined in all patients. Dermal remodeling was observed also on histologic examination of biopsied tissue after treatment. Carbon dioxide laser appears to be effective and well tolerated for the treatment of keloids, avoiding the adverse effects and lengthy recovery time. [ABSTRACT FROM AUTHOR]