Search

Repressing BET proteins' function using bromodomain inhibitors (BETi) has been shown to elicit antitumor effects by regulating the transcription of genes downstream of BRD4. We previously showed that BETi promoted cell death of triple-negative breast cancer (TNBC) cells. Here, we proved that BETi induce altered mitochondrial dynamics fitness in TNBC cells falling in cell death. We demonstrated that BETi treatment downregulated the expression of BCL-2, and proteins involved in mitochondrial fission and increased fused mitochondria. Impaired mitochondrial fission affected oxidative phosphorylation (OXPHOS) inducing the expression of OXPHOS-related genes, SDHa and ATP5a, and increased cell death. Consistently, the amount of mitochondrial DNA and mitochondrial membrane potential (∆Ψm) increased in BETi-treated cells compared to control cells. Lastly, BETi in combination with Metformin reduced cell growth. Our results indicate that mitochondrial dynamics and OXPHOS metabolism support breast cancer proliferation and represent novel BETi downstream targets in TNBC cells., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The medial unicompartmental knee arthroplasty (mUKA) has been recognized as an excellent treatment for medial knee osteoarthritis. The posterior tibial slope (PTS) is measured radiographically with the intramedullary axis (IMA) to the tibial baseplate on the sagittal plane radiograph. However, in most computer-navigated or robotic mUKAs, the PTS is set from a transmalleolar axis (TMA).The PTS difference was evaluatedbetween the sagittal TMA and the sagittal IMA of patients undergoing a CT-based primary robotic-assisted mUKA.We retrospectively reviewed the preoperative computed tomography (CT) scans taken according to the MAKO system protocol (Stryker) of 67 patients undergoing mUKAs. We measured the angular difference between the IMA and the TMA in the sagittal plane.Using the TMA to set the PTS the estimation of the slope of the medial tibial plateau would increase by an average of 1.9 ± 3.2 degreescompared to the IMA. Furthermore, in nineknees, PTS was decreased.Tibial components implanted with the help of a CT scan-based preoperative planning MAKO will show an average of 1.9 degrees more than those measured on sagittal radiographs potentially of concern for knee kinematics. A universal language is needed to standardize the slope calculation and the respective reference axis used., Competing Interests: None declared., (Thieme. All rights reserved.)

Proton magnetic resonance spectroscopy ( 1 H-MRS) of surgically collected tumor specimens may contribute to investigating cancer metabolism and the significance of the "total choline" ( t Cho) peak (3.2 ppm) as malignancy and therapy response biomarker. To ensure preservation of intrinsic metabolomic information, standardized handling procedures are needed. The effects of time to freeze (cold ischemia) were evaluated in (a) surgical epithelial ovarian cancer (EOC) specimens using high-resolution (HR) 1 H-MRS (9.4 T) of aqueous extracts and (b) preclinical EOC samples (xenografts in SCID mice) investigated by in vivo MRI-guided 1 H-MRS (4.7 T) and by HR- 1 H-MRS (9.4 T) of tumor extracts or intact fragments (using magic-angle-spinning (MAS) technology). No significant changes were found in the levels of 27 of 29 MRS-detected metabolites (including the t Cho profile) in clinical specimens up to 2 h cold ischemia, besides an increase in lysine and a decrease in glutathione. EOC xenografts showed a 2-fold increase in free choline within 2 h cold ischemia, without further significant changes for any MRS-detected metabolite (including phosphocholine and t Cho) up to 6 h. At shorter times (≤1 h), HR-MAS analyses showed unaltered t Cho components, along with significant changes in lactate, glutamate, and glutamine. Our results support the view that a time to freeze of 1 h represents a safe threshold to ensure the maintenance of a reliable t Cho profile in EOC specimens.

Revision of anterior cruciate ligament reconstruction (ACL-R) presents many challenges that are not encountered in the primary setting and, therefore, requires thorough preoperative planning. Recently, there has been growing evidence showing that combining the anterolateral ligament (ALL) reconstruction with ACL-R revision reduces the risk of postoperative ACL rupture and meniscal tears, and therefore, the ALL reconstruction becomes essential to a complex ACL revision. The technique that we describe is mainly used in the setting of complex ACL revision with extensive tunnel osteolysis associated with rotational instability of the knee. This article presents a technique for a one-stage complex ACL-R revision combined with ALL reconstruction using an Achilles tendon allograft with a bone plug., Competing Interests: The authors report no conflicts of interest in the authorship and publication of this article. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (© 2023 The Authors.)

Cell outer membranes contain glycosphingolipids and protein receptors, which are integrated into glycoprotein domains, known as lipid rafts, which are involved in a variety of cellular processes, including receptor-mediated signal transduction and cellular differentiation process. In this study, we analyzed the lipidic composition of human Dental Pulp-Derived Stem Cells (DPSCs), and the role of lipid rafts during the multilineage differentiation process. The relative quantification of lipid metabolites in the organic fraction of DPSCs, performed by Nuclear Magnetic Resonance (NMR) spectroscopy, showed that mono-unsaturated fatty acids (MUFAs) were the most representative species in the total pool of acyl chains, compared to polyunsatured fatty acids (PUFAs). In addition, the stimulation of DPSCs with different culture media induces a multilineage differentiation process, determining changes in the gangliosides pattern. To understand the functional role of lipid rafts during multilineage differentiation, DPSCs were pretreated with a typical lipid raft affecting agent (MβCD). Subsequently, DPSCs were inducted to differentiate into osteoblast, chondroblast and adipoblast cells with specific media. We observed that raft-affecting agent MβCD prevented AKT activation and the expression of lineage-specific mRNA such as OSX, PPARγ2, and SOX9 during multilineage differentiation. Moreover, this compound significantly prevented the tri-lineage differentiation induced by specific stimuli, indicating that lipid raft integrity is essential for DPSCs differentiation. These results suggest that lipid rafts alteration may affect the signaling pathway activated, preventing multilineage differentiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santilli, Fabrizi, Martellucci, Santacroce, Iorio, Pisanu, Chirico, Lancia, Pulcini, Manganelli, Sorice, Delle Monache and Mattei.)

The weak acid sorbic acid is a common preservative used in soft drink beverages to control microbial spoilage. Consumers and industry are increasingly transitioning to low-sugar food formulations, but potential impacts of reduced sugar on sorbic acid efficacy are barely characterised. In this study, we report enhanced sorbic acid resistance of yeast in low-glucose conditions. We had anticipated that low glucose would induce respiratory metabolism, which was shown previously to be targeted by sorbic acid. However, a shift from respiratory to fermentative metabolism upon sorbic acid exposure of Saccharomyces cerevisiae was correlated with relative resistance to sorbic acid in low glucose. Fermentation-negative yeast species did not show the low-glucose resistance phenotype. Phenotypes observed for certain yeast deletion strains suggested roles for glucose signalling and repression pathways in the sorbic acid resistance at low glucose. This low-glucose induced sorbic acid resistance was reversed by supplementing yeast cultures with succinic acid, a metabolic intermediate of respiratory metabolism (and a food-safe additive) that promoted respiration. The results indicate that metabolic adaptation of yeast can promote sorbic acid resistance at low glucose, a consideration for the preservation of foodstuffs as both food producers and consumers move towards a reduced sugar landscape., Competing Interests: None., (© 2023 The Authors.)

Purpose: Radical cystectomy (RC) is the standard treatment for high-risk non muscle-invasive bladder cancer (NMIBC) failing first BCG treatment. A second BCG course is an option for those patients who refuse RC or are not eligible for it, but its success rate is quite low. Aim of the present study was to determine whether the addition of intravesical electromotive drug administration of mytomicin-C (EMDA-MMC) improved the efficacy of second BCG course., Methods: Patients with high-risk NMIBC having failed first BCG treatment and having refused RC were offered a second BCG induction course either alone (group A) or combined with EMDA-MMC (group B). Recurrence-free survival (RFS), progression-free survival (PFS) and cancer-specific survival (CSS) were tested., Results: Of the 80 evaluable patients, 44 were in group A and 36 in group B; median follow-up was 38 months. RFS was significantly worse in group A whereas there was no difference in PFS and CSS between the two groups. Stratifying by disease stage, Ta patients receiving combined treatment had statistically better RFS and PFS survival than those receiving BCG only; this difference did not apply to T1 patients. Multivariable analysis confirmed that combined treatment was a significant predictor of recurrence and was close to predict progression. No tested variable was predictive of recurrence or progression in T1 tumours. Among those who underwent RC, CSS was 61.5% in those who had progression and 100% in those who remained with NMIBC., Conclusion: Combined treatment improved RFS and PFS only in patients with Ta disease., (© 2023. The Author(s).)

Background: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFβ, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer., Methods: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFβ. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival., Results: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment., Conclusions: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC., (© 2022. The Author(s).)

Background: Triple-Negative Breast Cancer (TNBC) is a subtype of breast cancer that differs from other types of breast cancers in the faster spread and worse outcome. TNBC presented limited treatment options. BET (Bromodomain and extra-terminal domain) proteins are epigenetic readers that control the expression of different oncogenic proteins, and their inhibition (BETi) is considered a promising anti-cancer strategy. Recent evidence demonstrated the involvement of BET proteins in regulation of metabolic processes., Methods: MDA-MB231 cells treated with JQ1 followed by RNA-sequencing analysis showed altered expression of lipid metabolic genes; among these, we focused on ATGL, a lipase required for efficient mobilization of triglyceride. Different in vitro approaches were performed to validate the RNA-sequencing data (qRT-PCR, immunofluorescence and flow cytometry). NMR (Nuclear Magnetic Resonance) was used to analyze the lipid reprogramming upon treatment. ATGL expression was determined by immunoblot and qRT-PCR, and the impact of ATGL function or protein knockdown, alone and in combination with BETi, was assessed by analyzing cell proliferation, mitochondrial function, and metabolic activity in TNBC and non-TNBC cells culture models., Results: TNBC cells treated with two BETi markedly increased ATGL expression and lipolytic function and decreased intracellular lipid content in a dose and time-dependent manner. The intracellular composition of fatty acids (FAs) after BETi treatment reflected a significant reduction in neutral lipids. The short-chain FA propionate entered directly into the mitochondria mimicking ATGL activity. ATGL KD (knockdown) modulated the levels of SOD1 and CPT1a decreasing ROS and helped to downregulate the expression of mitochondrial ß-oxidation genes in favor of the upregulation of glycolytic markers. The enhanced glycolysis is reflected by the increased of the mitochondrial activity (MTT assay). Finally, we found that after BETi treatment, the FoxO1 protein is upregulated and binds to the PNPLA2 promoter leading to the induction of ATGL. However, FoxO1 only partially prompted the induction of ATGL expression by BETi., Conclusions: The anti-proliferative effect achieved by BETi is helped by ATGL mediating lipolysis. This study showed that BETi altered the mitochondrial dynamics taking advantage of ATGL function to induce cell cycle arrest and cell death. Schematic representation of BETi mechanism of action on ATGL in TNBC cells. BETi induce the expression of FoxO1 and ATGL, lowering the expression of G0G2, leading to a switch in metabolic status. The induced expression of ATGL leads to increased lipolysis and a decrease in lipid droplet content and bioavailability of neutral lipid. At the same time, the mitochondria are enriched with fatty acids. This cellular status inhibits cell proliferation and increases ROS production and mitochondrial stress. Interfering for ATGL expression, the oxidative phenotypic status mildly reverted to a glycolytic status where neutral lipids are stored into lipid droplets with a consequent reduction of oxidative stress in the mitochondrial., (© 2023. The Author(s).)

Bariatric surgery (BS) is an effective intervention for severe obesity and associated comorbidities. Although several studies have addressed the clinical and metabolic effects of BS, an integrative analysis of the complex body response to surgery is still lacking. We conducted a longitudinal data study with 36 patients with severe obesity who were tested before, 6 and 12 months after restrictive BS for more than one hundred blood biomarkers, including clinical, oxidative stress and metabolic markers, peptide mediators and red blood cell membrane lipids. By using a synthetic data-driven modeling based on principal component and correlation analyses, we provided evidence that, besides the early, well-known glucose metabolism- and weight loss-associated beneficial effects of BS, a tardive, weight-independent increase of the hepatic cholesterol metabolism occurs that is associated with potentially detrimental inflammatory and metabolic effects. Canonical correlation analysis indicated that oxidative stress is the most predictive feature of the BS-induced changes of both glucose and lipids metabolism. Our results show the power of multi-level correlation analysis to uncover the network of biological pathways affected by BS. This approach highlighted potential health risks of restrictive BS that are disregarded with the current practice to use weight loss as surrogate of BS success., (© 2022. The Author(s).)

hMTH1 protects against mutation during oxidative stress. It degrades 8-oxodGTP to exclude potentially mutagenic oxidized guanine from DNA. hMTH1 expression is linked to ageing. Its downregulation in cultured cells accelerates RAS-induced senescence, and its overexpression in hMTH1-Tg mice extends lifespan. In this study, we analysed the effects of a brief (5 weeks) high-fat diet challenge (HFD) in young (2 months old) and adult (7 months old) wild-type (WT) and hMTH1-Tg mice. We report that at 2 months, hMTH1 overexpression ameliorated HFD-induced weight gain, changes in liver metabolism related to mitochondrial dysfunction and oxidative stress. It prevented DNA damage as quantified by a comet assay. At 7 months old, these HFD-induced effects were less severe and hMTH1-Tg and WT mice responded similarly. hMTH1 overexpression conferred lifelong protection against micronucleus induction, however. Since the canonical activity of hMTH1 is mutation prevention, we conclude that hMTH1 protects young mice against HFD by reducing genome instability during the early period of rapid growth and maximal gene expression. hMTH1 protection is redundant in the largely non-growing, differentiated tissues of adult mice. In hMTH1-Tg mice, expression of a less heavily mutated genome throughout life provides a plausible explanation for their extended longevity., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Introduction: Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice., Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group., Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale., Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns., (© 2022. The Author(s).)

Background: Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa)., Methods: We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment., Results: In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment., Conclusions: These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective.

The use of augmented reality (AR) and virtual reality (VR) for life support training is increasing. These technologies provide an immersive experience that supports learning in a safe and controlled environment. This review focuses on the use of AR and VR for emergency care training for health care providers, medical students, and nonprofessionals. In particular, we analyzed (1) serious games, nonimmersive games, both single-player and multiplayer; (2) VR tools ranging from semi-immersive to immersive virtual and mixed reality; and (3) AR applications. All the toolkits have been investigated in terms of application goals (training, assessment, or both), simulated procedures, and skills. The main goal of this work is to summarize and organize the findings of studies coming from multiple research areas in order to make them accessible to all the professionals involved in medical simulation. The analysis of the state-of-the-art technologies reveals that tools and studies related to the multiplayer experience, haptic feedback, and evaluation of user's manual skills in the foregoing health care-related environments are still limited and require further investigation. Also, there is an additional need to conduct studies aimed at assessing whether AR/VR-based systems are superior or, at the minimum, comparable to traditional training methods., (©Serena Ricci, Andrea Calandrino, Giacomo Borgonovo, Marco Chirico, Maura Casadio. Originally published in JMIR Serious Games (https://games.jmir.org), 23.03.2022.)

Background: Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC). The superiority of any BCG strain over another could not be demonstrated yet., Methods: Patients with NMIBCs underwent adjuvant induction ± maintenance schedule of intravesical immunotherapy with either BCG TICE or RIVM at two high-volume tertiary institutions. Only BCG-naïve patients and those treated with the same strain over the course of follow-up were included. One-to-one (1:1) propensity score matching (PSM) between the two cohorts was utilized to adjust for baseline demographic and tumor characteristics imbalances. Kaplan-Meier estimates and multivariable Cox regression models according to high-risk NMIBC prognostic factors were implemented to address survival differences between the strains. Sub-group analysis modeling of the influence of routine secondary resection (re-TUR) in the setting of the sole maintenance adjuvant schedule for the two strains was further performed., Results: 852 Ta-T1 NMIBCs ( n = 719, 84.4% on TICE; n = 133, 15.6% on RIVM) with a median of 53 (24-77) months of follow-up were reviewed. After PSM, no differences at 5-years RFS, PFS, and CSS at both Kaplan-Meier and Cox regression analyses were detected for the whole cohort. In the sub-group setting of full adherence to European/American Urology Guidelines (EAU/NCCN), BCG TICE demonstrated longer 5-years RFS compared to RIVM (68% vs. 43%, p = 0.008; HR: 0.45 95% CI 0.25-0.81)., Conclusion: When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to RIVM for RFS outcomes. However, no significant differences were detected for PFS and CSS, respectively.

Introduction: Sacrocolpopexy (SC) is the main treatment option for the repair of anterior and apical pelvic organ prolapse (POP). Indications and technical aspects are not standardized, and the question remains whether it is necessary to place a mesh on both anterior and posterior vaginal walls, particularly in cases with only minor or no posterior compartment prolapse. The present study aimed to compare the anatomical and functional outcomes of single anterior mesh only versus anterior and posterior mesh procedures in SC., Materials and Methods: Our prospectively maintained database on POP was used to identify patients who had undergone either abdominal or mini-invasive SC from January 2006 to October 2019. Patients with symptomatic or unmasked stress urinary incontinence (SUI) were not included in the study and were treated using the pubo-vaginal cystocele sling procedure. Objective outcomes included clinical evaluation of pre-existing or de novo POP by the halfway system and POP-q classifications, as well as the development of de novo SUI. Subjective outcomes were assessed using the Pelvic Floor Impact Questionnaire (PFIQ-7) with questions on bladder, bowel, and vaginal functions. Persistent or de novo constipation and overactive bladder were defined as bowel symptoms and urinary urgency/frequency/urinary incontinence after surgery., Results: Ninety-five women with symptomatic anterior and apical POP underwent SC. Forty-one patients were treated with only anterior vaginal mesh (group A), and 54 with anterior and posterior mesh (group B). There were no differences between the pre- and post-operative characteristics of the 2 groups. In group B, there were 2 blood transfusions, 1 wound dehiscence, and 3 mesh erosions/extrusion after abdominal SC (Clavien-Dindo II), and in group A, there was 1 ileal lesion after laparoscopic SC (Clavien-Dindo III). There were no differences between the 2 groups in either anatomical or functional outcomes during 3 years of follow-up., Conclusions: SC with single anterior vaginal mesh has similar results to SC with combined anterior/posterior mesh, regardless of the surgical approach. The single anterior mesh may reduce the risk of complications (mesh erosion/extrusion), and offers better subjective outcomes with improved quality of life. Anterior/posterior mesh may be justified in the presence of clinically significant posterior POP., (© 2021 S. Karger AG, Basel.)

Magnetic resonance imaging (MRI) offers excellent spatial and contrast resolution for evaluating a wide variety of pathologies, without exposing patients to ionizing radiations. Additionally, MRI offers reproducible diagnostic imaging results that are not operator-dependent, a major advantage over ultrasound. MRI is commonly used in pregnant women to evaluate, most frequently, acute abdominal and pelvic pain or placental abnormalities, as well as neurological or fetal abnormalities, infections, or neoplasms. However, to date, our knowledge about MRI safety during pregnancy, especially about the administration of gadolinium-based contrast agents, which are able to cross the placental barrier, is still limited, raising concerns about possible negative effects on both the mother and the health of the fetus. Contrast agents that are unable to cross the placenta in a way that is safe for the fetus are desirable. In recent years, some preclinical studies, carried out in rodent models, have evaluated the role of long circulating liposomal nanoparticle-based blood-pool gadolinium contrast agents that do not penetrate the placental barrier due to their size and therefore do not expose the fetus to the contrast agent during pregnancy, preserving it from any hypothetical risks. Hence, we performed a literature review focusing on contrast and non-contrast MRI use during pregnancy.

The first minute of life, the Golden Minute, has been defined as a critical window in which fundamental physiological processes occur for establishing spontaneous ventilation in a newborn. Resuscitation is more likely to succeed if it is performed properly and at the right time. In this scenario, simulation is an appropriate tool for training and evaluating the abilities of all staff working in the delivery room, as well as students. As simulations require a high degree of immersivity in order to be effective, the use of technologies like Virtual (VR) and mixed reality (MR) have garnered more interest in training. Currently, some VR and MR applications have been developed for adult life support training, but neonatal tools are still missing. To overcome this limitation, we present RiNeo MR, a prototype of a MR simulator for neonatal resuscitation training. The simulator consists of (i) a sensorized physical model of the newborn that allows monitoring chest compressions; (ii) a VR head mounted display that allows visualizing a virtual 3D model of the manikin and scenarios of the delivery and operating rooms. This enables students, and healthcare providers to be immersed in realistic hospital settings while performing life support procedures on the newborn manikin. Clinical Relevance-The newborn life support training (NLS) in facilities reduces term intrapartum-related deaths by 30%.

Massive hemorrhage remains the number one cause of preventable death in trauma worldwide. However, immediate intervention by a bystander can significantly improve the survival of the injured person. In this context, the tourniquets represent the most quick and effective devices for stopping arterial and venous blood flow. The aim of this study was to implement a system to detect the force applied by a tourniquet on a simulated limb, without blood flow. The system we designed is characterized by four low-cost force sensing resistors placed on each lower limb of a manikin, below the groin. Tests on 21 tourniquets, revealed that our system is able to detect the force applied for 60 minutes, also discriminating between turns. Hence, this system can be used to compare the performance of different types of devices, but also to assess proper tourniquet placement in trainees and trauma care providers, thus making it a versatile low-cost device.

Purpose: To determine the need for routine bladder biopsies (BBs) in assessing response to the induction cycle of intravesical bacillus Calmette-Guérin (BCG) for high-risk non-muscle-invasive bladder cancer (NMIBC)., Methods: Our prospectively maintained NMIBC database was queried to identify patients with high-risk disease (carcinoma in situ, high-grade Ta/T1) who underwent BBs after BCG induction cycle. Urine cytology, cystoscopy, and BBs findings were evaluated., Results: A total of 219 patients met the inclusion criteria. Urine cytology was positive in 20 patients and negative in 199; cystoscopy was positive in 35 patients, suspicious in 32 and normal in 152 patients. BBs yielded bladder cancer (BCa) in 43 (19.6%) patients, with a BCa rate of 9.3% in patients with negative cytology and cystoscopy as opposed to 38.0% in patients whereby one or both exams were suspicious/positive. The diagnostic accuracy of urine cytology, cystoscopy, and combined tests was 0.56, 0.70, and 0.71, respectively. The negative predictive value of combined tests was 90.7%. Performing BBs only in patients with positive cytology and/or positive/suspicious cystoscopy would have spared 140 (64%) patients to undergo this procedure while missing BCa in 13 (9.3%) of them, representing 30% of all BCa cases., Conclusion: Performing BBs only in patients with positive cytology and suspicious/positive cystoscopy would spare 64% of un-necessary BBs but miss a non-negligible number of BCas. While no data are available regarding the potential consequences of missing such BCas, such information should be taken into account in patient's counselling., (© 2021. The Author(s).)

Identification of markers predicting disease outcome is a major clinical issue for non-muscle invasive bladder cancer (NMIBC). The present study aimed to determine the role of the mitochondrial proteins Mitofusin-2 (Mfn2) and caseinolytic protease P (ClpP) in predicting the outcome of NMIBC. The study population consisted of patients scheduled for transurethral resection of bladder tumor upon the clinical diagnosis of bladder cancer (BC). Samples of the main bladder tumor and healthy-looking bladder wall from patients classified as NMIBC were tested for Mfn2 and ClpP. The expression levels of these proteins were correlated to disease recurrence, progression. Mfn2 and ClpP expression levels were significantly higher in lesional than in non-lesional tissue. Low-risk NMIBC had significantly higher Mfn2 expression levels and significantly lower ClpP expression levels than high-risk NMIBC; there were no differences in non-lesional levels of the two proteins. Lesional Mfn2 expression levels were significantly lower in patients who progressed whereas ClpP levels had no impact on any survival outcome. Multivariable analysis adjusting for the EORTC scores showed that Mfn2 downregulation was significantly associated with disease progression. In conclusion, Mfn2 and ClpP proteins were found to be overexpressed in BC as compared to non-lesional bladder tissue and Mfn2 expression predicted disease progression.

Urothelial carcinoma with an inverted growth pattern (UC-IGP) is a peculiar entity within the spectrum of urothelial lesions. While efforts have been made over the last few decades to unravel its carcinogenesis and relationship with conventional urothelial carcinoma, the exact classification of inverted urothelial lesions is a matter of debate. The morphological features of UC-IGP pose several issues in differential diagnosis with other mostly benign lesions. Various techniques, including immunohistochemistry, UroVysion, and many molecular methods, have been employed to study the exact nature of this lesion. The aim of this review is to provide a comprehensive overview of the morphological and immunophenotypical aspects of UC-IGP. Moreover, we present and discuss the immunohistochemical and molecular markers involved in diagnosis and prognosis of UC-IGP lesions.

Metabolism in acute myeloid leukemia (AML) cells is dependent primarily on oxidative phosphorylation. However, in order to sustain their high proliferation rate and metabolic demand, leukemic blasts use a number of metabolic strategies, including glycolytic metabolism. Understanding whether monocarboxylate transporters MCT1 and MCT4, which remove the excess of lactate produced by cancer cells, represent new hematological targets, and whether their respective inhibitors, AR-C155858 and syrosingopine, can be useful in leukemia therapy, may reveal a novel treatment strategy for patients with AML. We analyzed MCT1 and MCT4 expression and function in hematopoietic progenitor cells from healthy cord blood, in several leukemic cell lines and in primary leukemic blasts from patients with AML, and investigated the effects of AR-C155858 and syrosingopine, used alone or in combination with arabinosylcytosine, on leukemic cell proliferation. We found an inverse correlation between MCT1 and MCT4 expression levels in leukemic cells, and showed that MCT4 overexpression is associated with poor prognosis in AML patients. We also found that AR-C155858 and syrosingopine inhibit leukemic cell proliferation by activating two different cell-death related pathways, i.e., necrosis for AR-C155858 treatment and autophagy for syrosingopine, and showed that AR-C155858 and syrosingopine exert an anti-proliferative effect, additive to chemotherapy, by enhancing leukemic cells sensitivity to chemotherapeutic agents. Altogether, our study shows that inhibition of MCT1 or MCT4 impairs leukemic cell proliferation, suggesting that targeting lactate metabolism may be a new therapeutic strategy for AML, and points to MCT4 as a potential therapeutic target in AML patients and to syrosingopine as a new anti-proliferative drug and inducer of autophagy to be used in combination with conventional chemotherapeutic agents in AML treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saulle, Spinello, Quaranta, Pasquini, Pelosi, Iorio, Castelli, Chirico, Pisanu, Ottone, Voso, Testa and Labbaye.)

Aim: This study provides a critical literature review on state-of-the-art and novel strategies in the field of neoadjuvant treatments for muscle-invasive bladder cancer (MIBC)., Methods: A nonsystematic literature review was performed using PubMed, Scopus and Clinical Trials.gov to retrieve papers related to neoadjuvant treatments for MIBC over the past 15 years. Prospective and retrospective studies were included., Results: Platinum-based treatment is the gold standard and mainly consists of a combination of cisplatin with vinblastine, methotrexate, doxorubicin, gemcitabine, adriamycin or even epirubicin. The 5- year absolute overall survival benefit of MVAC is 5% and the absolute disease-free survival improves by 9%. CMV treatment is associated with a 10-year overall survival improving from 30% to 36% and a 16% reduction in mortality. Gemcitabine and cisplatin regimen provides complete response in 20% of cases, with non-inferior oncological outcomes compared to MVAC regimen. Recent prospective trials investigating neoadjuvant immunotherapy show a high rate of complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. The tyrosine kinase inhibitor pathway is being explored and could offer an interesting strategy to improve survival outcomes., Conclusion: Available evidence suggests better oncological outcomes for MIBC patients receiving neoadjuvant treatment before radical cystectomy. While MVAC remains the standard of care in cisplatin eligible patients, novel strategies are under development for cisplatin-ineligible patients, whereby immunotherapy seems to hold great promise., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To determine the impact of time to restaging transurethral resection (Re-TUR) on recurrence-free survival (RFS), progression-free survival (PFS), and cancer specific survival (CSS) of patients with high-grade T1 bladder cancer (BC) treated with intravesical Bacillus Calmette-Guerin (BCG)., Materials and Patients: Our prospectively maintained NMIBC databases were queried to identify patients with high-grade T1 BC who underwent Re-TUR before receiving intravesical BCG treatment (induction + 1-year maintenance). Patients were divided into three groups based on time to Re-TUR (group A: ≤ 6 weeks; group B: > 6-12 weeks; group C: > 12-18 weeks). Kaplan-Meier plots were used to estimate differences in RFS, PFS, and CSS. Multivariate Cox regression analysis was used to assess the impact of time to Re-TUR on oncological outcomes., Results: Overall, 269 high-grade T1 BC patients were eligible for the analysis. Nineteen (7.1%) had concomitant CIS. Median follow-up was 49.3 (IQR 25-65) months. Kaplan-Meier plots showed no differences in RFS, PFS, and CSS between the three groups. Multivariate Cox regression analysis showed that Group B had a slightly better RFS, while the other outcomes were not affected by time to Re-TUR., Conclusions: This is the first study testing the role of time to Re-TUR in a homogeneous population of patients with high-grade T1 BC who received complete BCG treatment. The study challenged the concept the sooner the Re-TUR the better, since time to Re-TUR did not significantly affect oncological outcomes.

Activation of the kynurenine pathway (KP), an important downstream effect of inflammation, is a driver of depression and neurodegeneration. Damage from the end product of KP activation, quinolinic acid, may be responsible specifically for impairment in hippocampally mediated memory function, among its effects. We hypothesized that associative memory - the ability to recall relationships between items - would be sensitive to KP activation because it is heavily dependent on the hippocampus. We tested a sample of N ​= ​80 adults with unmedicated depression using a face-name task which assesses the ability to recognize, as well as to recall correct pairings, of faces and names. Plasma samples were analyzed for KP metabolites - tryptophan (TRP), kynurenine (KYN), quinolinic acid (QUIN) and kynurenic acid (KYNA). Using linear models we examined whether the KYN/TRP and QUIN/KYNA ratios predicted performance of recognition memory and associative memory, accounting for item type and the number of learning exposures to items (1 vs. 3). We found that for rearranged items viewed three times, associative memory performance was inversely related to the QUIN/KYNA ratio (p ​= ​0.01, p ​= ​0.001 adjusted for age, gender and race/ethnicity). Recognition memory was not associated with KP activation. The results support our hypothesis that KP activation most sensitively impacts hippocampally mediated memory function., Competing Interests: Authors MC, JC, IS, CC, SM, and PR have nothing to declare. RD has received honoraria from Pfizer USA and from Danone Nutricia Research France for work that is not related to the present study. MHT has received funds from Allergan, Alto Neuroscience Inc, Applied Clinical Intelligence LLC, Axsome Therapeutics, Boegringer Ingelheim, Engage Health Media, GreenLight VitalSign6 Inc, Janssen, 10.13039/501100013327Lundbeck Research 10.13039/100011408USA, 10.13039/100009947Merck Sharp & Dohme Corp., Navitor Pharmaceutical Inc, Otsuka, Perception Neuroscience, Pharmerit International, SAGE Therapeutics, and Signant Health for work consulting and/or advisory board service not related to the present study. He has received funds for editorial work from the 10.13039/100005386American Psychiatric Association. Dr. Toups has received funds for service on a Data, Safety and Monitory Board from Otsuka for work not related to the present study., (© 2020 The Authors.)

Thyroid cancer cells demonstrate an increase in oxidative stress and decreased antioxidant action, but the effects of this increased oxidative stress on cell function remain unknown. We aimed to identify changes in the metabolism of thyroid cancer cells caused by oxidative stress, using proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. Samples of thyroid cancer and healthy thyroid tissue were collected from patients undergoing thyroidectomy and analyzed with 1 H-NMR spectroscopy for a wide array of metabolites. We found a significant increase in lactate content in thyroid cancer tissue compared to healthy tissue. Metabolomic analysis demonstrated significant differences between cancer tissue and healthy tissue, including an increase in aromatic amino acids, and an average decrease in citrate in thyroid cancer tissue. We hypothesize that these changes in metabolism may be due to an oxidative stress-related decrease in activity of the Krebs cycle, and a shift towards glycolysis in cancer tissue. Thus, thyroid cancer cells are able to reprogram their metabolic activity to survive in conditions of high oxidative stress and with a compromised antioxidant system. Our findings, for the first time, suggested a connection between oxidative stress and the alteration of the metabolic profile in thyroid tumors., Competing Interests: The authors declare no conflict of interest.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a high-grade neuroendocrine tumor with distinct pathological features, usually portending an aggressive clinical behavior in comparison to conventional urothelial carcinoma. Due to its low prevalence, little is known about its clinical management and there is no current standard of care. The aim of this review was to summarize the current knowledge about LCNEC of the bladder, ureter and kidney, with relevance to diagnostic, prognostic and therapeutic issues, through a systematic analysis of clinical, pathological and outcome data retrieved from the literature., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mutations at the LYS3 locus in barley have multiple effects on grain development, including an increase in embryo size and a decrease in endosperm starch content. The gene underlying LYS3 was identified by genetic mapping and mutations in this gene were identified in all four barley lys3 alleles. LYS3 encodes a transcription factor called Prolamin Binding Factor (PBF). Its role in controlling embryo size was confirmed using wheat TILLING mutants. To understand how PBF controls embryo development, we studied its spatial and temporal patterns of expression in developing grains. The PBF gene is expressed in both the endosperm and the embryos, but the timing of expression in these organs differs. PBF expression in wild-type embryos precedes the onset of embryo enlargement in lys3 mutants, suggesting that PBF suppresses embryo growth. We predicted the down-stream target genes of PBF in wheat and found them to be involved in a wide range of biological processes, including organ development and starch metabolism . Our work suggests that PBF may influence embryo size and endosperm starch synthesis via separate gene control networks., Competing Interests: None., (© 2020 The Authors.)

In Triticeae endosperm (e.g. wheat and barley), starch granules have a bimodal size distribution (with A- and B-type granules) whereas in other grasses the endosperm contains starch granules with a unimodal size distribution. Here, we identify the gene, BGC1 (B-GRANULE CONTENT 1), responsible for B-type starch granule content in Aegilops and wheat. Orthologues of this gene are known to influence starch synthesis in diploids such as rice, Arabidopsis, and barley. However, using polyploid Triticeae species, we uncovered a more complex biological role for BGC1 in starch granule initiation: BGC1 represses the initiation of A-granules in early grain development but promotes the initiation of B-granules in mid grain development. We provide evidence that the influence of BGC1 on starch synthesis is dose dependent and show that three very different starch phenotypes are conditioned by the gene dose of BGC1 in polyploid wheat: normal bimodal starch granule morphology; A-granules with few or no B-granules; or polymorphous starch with few normal A- or B-granules. We conclude from this work that BGC1 participates in controlling B-type starch granule initiation in Triticeae endosperm and that its precise effect on granule size and number varies with gene dose and stage of development., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Although several drugs are available to treat recurrences of human epithelial ovarian cancer (EOC), clinical responses often remain short lived and lead to only marginal improvements in patients' survival. One of the new drugs proposed for recurrent platinum-resistant EOC patients is trabectedin (Trab), a marine-derived antitumor agent initially isolated from the tunicate Ecteinascidia turbinata and currently produced synthetically. Predictive biomarkers of therapy response to this drug and the potential use of non-invasive functional MRI and MRS approaches for an early assessment of Trab efficacy have not yet been evaluated, although they might be relevant for improving the clinical management of EOC patients. In the present work we combined functional and spectroscopic magnetic resonance technologies, such as in vivo diffusion-weighted MRI and 1 H MRS, with ex vivo high resolution MRS (HR-MRS) metabolomic analyses, with the aim of identifying new pharmacodynamic markers of Trab effectiveness on well characterized, highly aggressive human SKOV3.ip (a HER2-enriched cell variant derived from SKOV3 cells) EOC xenografts. In vivo treatment with Trab (three consecutive weekly 0.2 mg/kg i.v. injections) resulted in the following: (1) a significant reduction of in vivo tumor growth, along with the formation in cancer lesions of diffuse hyper-intense areas detected by T 2 -weighted MRI and attributed to necrosis, in agreement with histopathology findings; (2) significant increases in the apparent diffusion coefficient mean and median values versus saline-treated control tumors; and (3) a significant reduction in the choline-containing metabolites' signal detected by quantitative in vivo MRS. Multivariate and quantitative HR-MRS analyses on ex vivo tissue samples revealed Trab-induced alterations in phospholipid and glucose metabolism identified as a decrease in phosphocholine and an increase in lactate. Collectively, these data identify Trab-induced functional MRI and MRS alterations in EOC models as a possible basis for further developments of these non-invasive imaging methods to improve the clinical management of EOC patients., (© 2018 John Wiley & Sons, Ltd.)

Intravesical instillation of Bacille Calmette-Guèrin (BCG) is the standard adjuvant treatment for high-risk non muscle invasive bladder cancer (NMIBC). Since its mechanism of action is supposed to be linked to the immune system efficiency and senescence could negatively affect this efficiency, BCG efficacy in the elderly has been questioned. This study aimed to assess the impact of age on BCG efficacy and safety in patients with high-grade T1 bladder cancer (BC).Among 123 patients with high-grade T1 BCG scheduled for BCG treatment, 82 were <75 year-old (group A) and 41 were ≥75 year-old (group B). Follow-up: urine cytology and cystoscopy every 3 months for the first 2 years, every 6 months for the third year, and then yearly. Tumor recurrence was defined as pathological evidence of disease at the bladder biopsy; tumor progression was defined as pathological shift to muscle invasive disease at the bladder biopsy or the imaging techniques showing recurrent BC and distant metastasis likely related to it.The median follow-up was 65 months (range 11-152). Recurrence occurred in 35 patients, 19 (23.2%) in the group A and 16 (39%) in the group B. Progression occurred in 18 patients, 12 (14.6%) in the group A and 6 (14.6%) in the group B. Recurrence free rate was similar in both groups up to 2 years. The 5 years progression rate was almost the same in both groups A and B (85.9% vs 84.7%), whereas the 5 years cancer-specific survival (CSS) was 92.6% in the group A and 85.4% in the group B. Of the 18 patients with progression, 11 underwent cystectomy; 12 patients died because of their BC. Kaplan-Meier plots pointed out no difference in recurrence-free, progression-free, and CSS between the 2 groups. Adverse events were similar in the 2 groups. Only 4 (3.3%) patients, 2 (2.4%) in the group A and 2 (4.8%) in the group B, experienced mild adverse reactions compatible with treatment.Elderly patients with high-grade T1 BC are not poorer candidates to BCG treatment, as they had similar benefit and adverse reactions than those aging ≥75 years.

Simulation is a powerful learning tool, as it allows gaining direct experience in a controlled and repeatable way. However, the simulation is effective when it is able to reproduce the real conditions and when the user feels him/herself immersed and present in the situation. With the aim of improving these critical points, we propose an immersive virtual reality system for first-aid handling. Specifically, we increase the visual realism of medical mannequins and the contextualization, and we add the touch feedback by mapping the real mannequin into its virtual representation. Moreover, the interaction is performed by using a virtual representation of the users own hands by allowing a more realistic execution of tasks. The results show a good accuracy in the mapping between the real and the virtual mannequin, and a high degree of presence for both the control group and the medical one. These results and the low values of simulator sickness reported during the experiment are a good starting point for the use of the proposed mixed reality system in simulation scenarios.

Re-staging transurethral resection, the so-called repeat TUR (Re-TUR), is mandatory in case of incomplete first transurethral resection of bladder tumor (TURBT). In completely resected high grade T1 tumors, Re-TUR is recommended but question remains whether it provides advantages in terms of recurrence-free survival (RFS), progression-free survival (PFS), and cancer specific survival (CSS). The present study aimed to determine whether Re-TUR improves such outcomes in patients with completely resected high-grade T1 bladder cancer (BC). We queried our prospectively maintained database to identify patients with completely resected high-grade T1 BC who underwent (Group A) or not (Group B) Re-TUR before starting intravesical instillations of Bacillus Calmette-Guerin (BCG). The impact of Re-TUR as well as of other tested variables on RFS, PFS, and CSS was tested by Kaplan-Meier method and Log-rank testing. A total of 118 patients underwent Re-TUR, which pointed out no BC in 61 (51.7%), NMIBC in 54 (45.8%) and pT2 disease in 3 (2.5%). The 3 patients with pT2 disease underwent cystectomy, whereas all others were offered BCG treatment. Forty-two patients refused BCG treatment while 2 did not complete it; therefore, Group A (Re-TUR before BCG treatment) consisted of 71 patients whereas Group B consisted of 40 patients who refused Re-TUR but completed BCG treatment. Mean follow-up was 60 months (range 12-142). Kaplan-Meier curves and Log-rank testing showed no difference in RFS, PFS and CSS between patients who had (Group A) or had not (Group B) Re-TUR before starting BCG treatment. Our findings suggest that a Re-TUR in patients with a completely resected high-grade T1 BC does not translate into a better oncological outcome. Given its impact on both patients and healthcare system, the need for Re-TUR in completely resected high grade T1 BC should be further investigated into the framework of a randomized study.

Background: The aims of this study were to identify the source and the transmission pathway for a Staphylococcal Scalded Skin Syndrome (SSSS) outbreak in a maternity setting in Italy over 2 months, during 2014; to implement appropriate control measures in order to prevent the epidemic spread within the maternity ward; and to identify the Methicillin-Resistant Staphylococcus aureus (MRSA) epidemic clone., Methods: Epidemiological and microbiological investigations, based on phenotyping and genotyping methods, were performed. All neonates involved in the outbreak underwent clinical and microbiological investigations to detect the cause of illness. Parents and healthcare workers were screened for Staphylococcus aureus to identify asymptomatic carriers., Results: The SSSS outbreak was due to the cross-transmission of a rare clone of ST5-CA-MRSA-SCCmecV-spa type t311, exfoliative toxin A-producer, isolated from three neonates, one mother (from her nose and from dermatological lesions due to pre-existing hand eczema) and from a nurse (colonized in her nose by this microorganism). The epidemiological and microbiological investigation confirmed these as two potential carriers., Conclusions: A rapid containment of these infections was obtained only after implementation of robust swabbing of mothers and healthcare workers. The use of molecular methodologies for typing was able to identify all carriers and to trace the transmission.

A newborn girl of 36 weeks gestation was noted to have several anomalies, including bilateral low ear attachment with ear pinnae hypertrichosis, left preauricular pit, micrognathia, short lingual frenulum, and short neck. Pregnancy history revealed poorly controlled maternal gestational diabetes (GD). Localized hypertrichosis of the ear pinnae may represent a potential marker of GD and thereby alert physicians to suspect other potentially GD-associated conditions such as macrosomia, asphyxia, respiratory distress, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia, hypertrophic cardiomyopathy, and congenital anomalies, particularly those involving the central nervous system., (© 2015 Wiley Periodicals, Inc.)

Aim: Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis., Results: CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-α were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls., Conclusions: Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis., (© 2013 John Wiley & Sons A/S.)

Objective: To evaluate technology-assisted programs to help a man with pervasive motor disabilities and an adolescent with multiple disabilities manage the use of a radio and a special messaging system, respectively., Method: The technology for the man (Study I) involved a modified radio device, an electronic control unit, an amplified MP3 player with verbal questions about radio operations (changes), and an optic microswitch. This allowed the man to respond to the questions and carry out operations through minimal chin movement. The technology for the adolescent (Study II) involved a net-book computer fitted with specifically designed software, a global system for mobile communication (GSM) modem, and an optic microswitch. This allowed the adolescent to select the persons to whom he wanted to send messages and the messages to send them, and to listen to messages sent to him., Results: The data showed that both programs were effective, with the two participants learning to use the radio and the messaging system, respectively., Conclusion: Technology-assisted programs may represent useful tools for providing persons with pervasive and multiple disabilities leisure and communication opportunities.

Background: Ascariasis continues to be one of the most important parasitic diseases in terms of its burden and complications in children in the developing world., Methods: Case report and literature review (Medline, SCI, and LILACS)., Results: We report herein a case in which a Paraguayan infant presented with one of these complications: An intestinal obstruction due to Ascaris lumbricoides being diagnosed during surgery. The patient was managed with a conservative protocol for the extraction of the parasites using liquid petrolatum administered through a nasogastric tube followed with extensive water irrigation through the tube, in conjunction with the administration of piperazine as antiparasitic treatment., Conclusions: This case, as with others reported previously, shows that this complication can be managed successfully without major intestinal surgery. Early recognition of this condition, based on local prevalence, can prevent serious surgical complications, morbidity, and mortality associated with intestinal obstruction due to A. lumbricoides.

Among possible determinants of vascular events, the role of high lipoprotein(a) (Lp[a]) serum levels represents a still uncertain independent risk factor in elderly populations. Moreover, the cumulative incidence of nonfatal vascular events due to high Lp(a) serum levels is conditioned by the competing risk of death from any causes that are a function of age. After a 6.3-year median follow up, we tested the competing risks of all-cause mortality, cumulative fatal-nonfatal stroke events, cumulative fatal-nonfatal coronary artery disease (CAD) events, and nonfatal stroke or CAD events due to high Lp(a) serum levels in a population-based, prospective study conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Of 704 elderly individuals (65-84 years), 372 (169 women and 203 men) agreed to participate in the study. As compared with those in the lowest Lp(a) tertile serum levels, subjects in the highest tertile (>20 mg/dL) had a higher partially adjusted risk of nonfatal CAD (hazard ratio, 4.19; 95% confidence interval [CI], 1.36-12.94) and nonfatal stroke (hazard ratio, 3.38; 95% CI, 1.00-11.56). Compared with those in the lowest tertile, subjects in the highest tertile had a higher fully adjusted risk of nonfatal CAD (hazard ratio, 3.41; 95% CI, 1.08-10.78). Finally, overall no statistically significant association was found between Lp(a) and the risk of all-cause mortality, cumulative fatal-nonfatal stroke, and cumulative fatal-nonfatal CAD events. In our population, Lp(a) was not a significant independent predictor of stroke and death from all causes, but it was an independent predictor of nonfatal CAD. Finally competing risk, conditioning the timing and occurrence of vascular events in our study population, could be a correct approach for evaluating the role of Lp(a) lipoprotein in vascular disease among elderly people.

Setting: Public health care services in the provinces of Buenos Aires, Santa Fe, Jujuy and Santa Cruz, Argentina., Objective: To evaluate delays in tuberculosis (TB) diagnosis and treatment and associated risk factors in departments and administrative areas of four Argentine provinces., Design: Cross-sectional survey including retrospective medical record review and patient interviews., Results: A total of 243 patients with smear-positive pulmonary TB and a mean age of 40 years were included in the study. The mean diagnostic delays were as follows: total delay 92.1 days (median 62.0); patient delay 58.8 days (median 31); health service delay 32.6 days (median 12.5). The mean treatment delay was 0.9 days (median 0). Associations were observed between patient delays of >30 days and residence in Jujuy, age >50 years, dependence on transport to the nearest public health service due to distance and presence of cough. The >60-day total diagnosis delay was associated with age >50 years and need for transport to the nearest public health service., Conclusion: Diagnostic delay is an important problem in the areas studied, with patient delay being of most concern. Patient delay was associated with age >50 years, dependence on transport to the nearest public health service due to distance and presence of cough.

Objective: The spleen is the most frequently involved organ in abdominal blunt traumas. In the last decade the treatment has changed from an exclusive surgical approach to a conservative approach. We report our experience in the last twenty years., Methods: Between 1983-2003, 54 patients with blunt abdominal traumas and isolated injury have been treated. The age at the time of diagnosis was 3 to 16 years (mean, 6.5). The diagnosis was made clinically and with imaging techniques (radiographic assessment, scintigraphy, US, CT). In all cases, a conservative treatment was started with continuous vital parameters monitoring, blood red cells count, hemoglobin, hematocrit; volume infusion and when necessary hemo-transfusion. Clinical follow-up and US monitoring were performed for six months after the trauma., Results: In the period 1983-1993 a conservative treatment was tried in 23 patients; in 15 cases it was successfully, in 8 cases a laparotomy with splenectomy was necessary due to hemodinamic instability. In the second decade we observed 31 patients, all had been treated conservatively. The mean hospital stay was of 12 days with no deaths., Conclusions: Conservative treatment for splenic injuries in patients with hemodinamic stability is nowadays the treatment choice. Constantly monitoring of clinical, laboratory parameters and use of modern imaging techniques allows to follow the evolution of the lesion and to avoid, in most cases, a surgical treatment.

Group A rotavirus infections were detected in 93 of 410 fecal samples from children with acute diarrhea, admitted in three main hospitals of Asunción, Paraguay, from August 1998 to August 2000. Most of the rotavirus-infected patients were admitted during the winter season in the three epidemic years. The rotavirus infection rate was highest in infants from 6 to 23 months of age. In the 93 samples examined, 10 different rotavirus electropherotypes were recognized, but two of them largely predominated. Only one sample showed a short electropherotype pattern, thus indicating a minor involvement of the rotavirus subgroup I in rotaviral acute diarrhea in the area and the time during which the survey was carried out.

Microscopy with the Ziehl-Neelsen (ZN) stain is frequently negative in paucibacillary tuberculosis (TB) so that the treatment must be started and continued until the culture results confirm or not the disease. LCx Mycobacterium tuberculosis Assay (Abbott, Lab.) uses the ligase chain reaction for direct amplification of DNA and rapid detection of M. tuberculosis Complex (MTB) in clinical specimens. We evaluated the usefulness of the LCx assay on 1,203 clinical samples: 737 respiratory and 466 extrapulmonary specimens. The LCx results were compared with those obtained by ZN and cultures on solid media and Mycobacteria Growth Indicator Tube (MGIT, Becton Dickinson, Argentina). Since detection and identification of MTB are simultaneously made by the LCx assay, a total of 145 out of 183 patients (79.2%) had a confirmed TB diagnosis in two working days. Positive culture results were predicted in 122 out of 160 cases (76.3%) by LCx and in 70 (43.8%) by ZN as well. The sensitivity (S) and specificity (ES) of LCx assay in ZN positive cases were 93.4% and 100.0% while in ZN negative cases they were 68.0% and 98.6%. The overall S and ES were 79.2% and 98.7%, respectively. We conclude that the LCx assay is a rapid and sensitive technique, which can be a helpful diagnostic tool mainly for paucibacillary TB in reference laboratories.

Unlabelled: Telemedicine is the transmission of medical notices and images among remote sites, that uses adequate audio-video systems., Objective: To increase the quality and the amount of medical informations, avoiding unnecessary carriages. Among main fields of interest in Telemedicine, monitoring of cardiovascular parameters and medical emergency represent situations that need to be promptly and appropriately approached. In such a similar conditions, a preliminary transmission to III level Health Institutions of informations as Electrocardiograms or even Echocardiograms may play an essential role in the diagnosis, prognosis and treatment of emergent cardiovascular disease., Methods: Since March 1998, an Audio-Video PC-based system that uses integrated services digital network (ISDN) at a bandwith of 384 Kbps, was installed at Pediatric Cardiac Surgery Department of Giovanni XXIII Hospital, Bari, Italy. On July 1999, thanks to Research Funds of the Health Ministry of Italy, similar audio-video systems that use ISDN were installed in the main pediatric institutions of provinces of Puglia and linked in a wide area network., Results: We report the experience of Telemedicine of a Department of Pediatric Cardiology and Cardiac Surgery, and we try to analyze its impact on improvement of quality of care, once employed in provincial field.

Hemimegalencephaly (HME) is a rare neuronal migration anomaly, rarely associated with hemihypertrophy or some other somatic malformation; it can coexist with intracranial arteriovenous shunts which cause cardiac failure. We report a rare case associated with hemihypertrophy of the face, trunk and limbs and malformation of the feet. The neuroradiological findings are underlined and the differential diagnoses discussed.