Post-Coronavirus Disease 2019 Pandemic Antimicrobial Resistance.

Background And Aim: Antimicrobial resistance (AMR) is a chronic issue of our Westernized society, mainly because of the uncontrolled and improper use of antimicrobials. The coronavirus disease 2019 (COVID-19) pandemic has triggered and expanded AMR diffusion all over the world, and its clinical and therapeutic features have changed. Thus, we aimed to review evidence from the literature on the definition and causative agents of AMR in the frame of the COVID-19 post-pandemic era.

Human Precision-Cut Liver Slices: A Potential Platform to Study Alcohol-Related Liver Disease.

Alcohol-related liver disease (ALD) encompasses a range of pathological conditions that are complex to study at the clinical and preclinical levels. Despite the global burden of ALD, there is a lack of effective treatments, and mortality is high. One of the reasons for the unsuccessful development of novel therapies is that experimental studies are hindered by the challenge of recapitulating this multifactorial disorder in vitro, including the contributions of hepatotoxicity, impaired lipid metabolism, fibrosis and inflammatory cytokine storm, which are critical drivers in the pathogenesis of ALD in patients and primary targets for drug development.

Patient-derived precision cut tissue slices from primary liver cancer as a potential platform for preclinical drug testing.

Background: The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities.

Giant mitochondria in human liver disease.

This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories.

Human Immunocompetent Model of Neuroendocrine Liver Metastases Recapitulates Patient-Specific Tumour Microenvironment.

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue.

Extracellular Vesicle-Mediated Mitochondrial Reprogramming in Cancer.

Altered metabolism is a defining hallmark of cancer. Metabolic adaptations are often linked to a reprogramming of the mitochondria due to the importance of these organelles in energy production and biosynthesis. Cancer cells present heterogeneous metabolic phenotypes that can be modulated by signals originating from the tumor microenvironment.

Interplay between Cellular and Non-Cellular Components of the Tumour Microenvironment in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Currently, treatments available for advanced HCC provide dismal chances of survival, thus there is an urgent need to develop more effective therapeutic strategies. While much of the focus of recent decades has been on targeting malignant cells, promising results have emerged from targeting the tumour microenvironment (TME).

Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity.

Background And Aims: Immunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.

Methods: In Alcoholic Hepatitis (AH; = 19), alcohol-related cirrhosis (ARC; = 53) and healthy control (HC; = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-blood soluble-CR expression upon bacterial challenge.

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease.

Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown.

Deficient IL-6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis.

Mechanisms underlying alcohol-induced liver injury and its progression still remain incompletely understood. Animal models can only address some aspects of the pathophysiology that requires studies directly in humans, which are scarce. We assessed liver inflammatory and immune responses at early stages of alcoholic liver disease in a unique cohort of alcohol-dependent patients undergoing a highly standardized alcohol withdrawal program.

41 Cases of Treatment of Cranial Cruciate Ligament Rupture with Porous TTA: Three Years of Follow Up.

Tibial Tuberosity Advancement (TTA) is a surgical technique based on a linear osteotomy that determines a cranial advancement of the tibial tuberosity in patients suffering from cranial cruciate ligament rupture (CCL). The aim is to neutralize the cranial tibial thrust (CTT) and to reach a 90° angle between the patellar tendon and the tibial plateau with a physiological knee extension of 135°. In our study, a Ti6AI4V ELI (Titanium Aluminium Vanadium) titanium scaffold for the Porous TTA, with excellent properties of osteointegration and osteoconduction when subjected to cyclic loading has been adopted.

Dynamin-1-Like Protein Inhibition Drives Megamitochondria Formation as an Adaptive Response in Alcohol-Induced Hepatotoxicity.

Despite the growing global burden of alcoholic liver diseases, therapeutic options are limited, and novel targets are urgently needed. Accumulating evidence suggests that mitochondria adapt in response to ethanol and formation of megamitochondria in the livers of patients is recognized as a hallmark of alcoholic liver diseases. The processes involved in ethanol-induced hepatic mitochondrial changes, the impact on mitochondria-shaping proteins, and the significance of megamitochondria formation remain unknown.

Precision-cut liver slices: a versatile tool to advance liver research.

Human precision-cut liver slices represent a robust and versatile ex vivo model which retains the complex and multi-cellular histoarchitecture of the hepatic environment. As such, they represent an ideal model to investigate the mechanisms of liver injury and for the identification of novel therapeutic targets. Schematic overview to highlight the utility of precision-cut liver slices as a relevant and versatile ex-vivo model of liver disease.

The development and testing of a module on child functioning for identifying children with disabilities on surveys. I: Background.

This is the first of three papers that will document the development of a survey module on child functioning developed by UNICEF in collaboration with the Washington Group on Disability Statistics (WG), and demonstrate - both conceptually and through test results - the strengths of that module compared with alternative tools for identifying children with disabilities in household surveys. This first paper in the series sets the background and reviews the literature leading to the development of the UNICEF/WG Child Functioning Module (CFM) and presents the WG Short Set of questions (WG-SS) and the Ten Question Screening Instrument (TQSI) as precursors, outlining some of their shortcomings and how the UNICEF/WG CFM was designed to meet those challenges. Subsequent articles will summarize results from the cognitive and field testing of the CFM including comparisons with results derived from the TQSI and the WG-SS.

Measuring child functioning: the Unicef/ Washington Group Module.

This paper describes the development of a standard survey instrument designed to identify children with functional difficulties through censuses and surveys. Using the World Health Organization’s (WHO) International Classification of Functioning, Disability, and Health (ICF) as a conceptual framework the Washington Group on Disability Statistics (WG) and UNICEF, in collaboration with experts, developed a survey module on child functioning for 2–4 and 5–17 year olds, which was piloted in different countries. To-date, the module has been used in four population surveys, including the Children and Women National Survey in Mexico (ENIM 2015).

Effects of the functional orthopaedic therapy on masticatory muscles activity.

Background: The purpose of this study was to examine surface electromyographic (sEMG) activity of masticatory muscles before and after functional orthopaedic therapy with Sander appliance.

Material And Methods: Ten adolescents (5 girls, 5 boys) with an Angle Class II, division I malocclusion, 9-13 years old, were submitted to sEMG before and after functional orthopaedic therapy. To verify the neuromuscular equilibrium, the standardized EMG activities of right and left masseter and anterior temporal muscles were recorded during maximum voluntary clench, and analysed calculating: POC (index of the symmetric distribution of the muscular activity determined by the occlusion); TC (index of presence of mandibular torque) and Ac (index suggesting the position of occlusal barycentre).

Longitudinal effects of rapid maxillary expansion on masticatory muscles activity.

Background: To investigate the modifications induced by rapid maxillary expansion (RME) on the electromyographic (EMG) activities of the anterior temporal and superficial masseter muscles, in patients without pre-treatment EMG alterations.

Material And Methods: Twenty-one patients with unilateral posterior cross-bite selected from the orthodontic department of the University of L'Aquila (Italy), were enrolled. There was no control group in this study since each subject acted as a control of her/himself.

Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis.

Introduction: Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis.

Orthodontic management of bilateral maxillary canine-first premolar transposition and bilateral agenesis of maxillary lateral incisors: a case report.

Introduction: Maxillary canine-first premolar transposition (Mx.C.P1) is an uncommon dental positional anomaly that may create many orthodontic problems from both esthetic and functional points of view.

Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis.

Background & Aims: Susceptibility to bacterial infection is a feature of alcohol-related liver disease. Programmed cell death 1 (PD1), the T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3, also known as hepatitis A virus cellular receptor 2), and their respective ligands-CD274 (also known as PD ligand 1 [PDL1]) and galectin-9-are inhibitory receptors that regulate the balance between protective immunity and host immune-mediated damage. However, their sustained hyperexpression promotes immune exhaustion and paralysis.

NIM811, a cyclophilin inhibitor without immunosuppressive activity, is beneficial in collagen VI congenital muscular dystrophy models.

Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are inherited muscle diseases due to mutations in the genes encoding the extracellular matrix protein collagen (Col) VI. Opening of the cyclosporin A-sensitive mitochondrial permeability transition pore (PTP) is a causative event in disease pathogenesis, and a potential target for therapy. Here, we have tested the effect of N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclophilin inhibitor, in a zebrafish model of ColVI myopathy obtained by deletion of the N-terminal region of the ColVI α1 triple helical domain, a common mutation of UCMD.

A glutamine synthetase inhibitor increases survival and decreases cytokine response in a mouse model of acute liver failure.

Background: Acute liver failure (ALF) can be induced in mice by administering Escherichia coli lipopolysaccharide (LPS) and D-galactosamine (D-GalN), which induce an inflammatory response involving tumour necrosis factor (TNF)-α production and a hepatocyte-specific transcriptional block. Under these conditions, binding of TNF-α to its cognate receptor on hepatocytes eventually leads to their apoptosis.

Aims: As part of an effort to identify drugs to treat this disease model, we have investigated whether the glutamine synthetase inhibitor methionine sulfoximine (MSO) could play a protective role, given its effectiveness in the inhibition of brain swelling associated with hyperammonaemia.

Activities of masticatory muscles in patients before orthognathic surgery.

Aim: To compare the influence of occlusal versus craniofacial characteristics on the functionality of the stomatognathic apparatus.

Materials And Methods: Two groups of subjects were selected: 27 patients (13 women and 14 men), 18 to 42 years old, all candidates for orthognathic surgery, 7 with prognathic syndrome and 20 with progenic syndrome; and 26 healthy young adults (13 women and 13 men) of corresponding age (control group). To verify the neuromuscular equilibrium induced by occlusion, the electromyographic activities of both right and left masseter and anterior temporal muscles were recorded and analyzed, calculating the percentage overlapping coefficient (an index of the symmetric distribution of the muscular activity determined by the occlusion) and TORS (index of the presence of mandibular torque).

Activities of masticatory muscles in patients after orthognathic surgery.

Aim: To evaluate left and right masseter and anterior temporalis muscle activity in patients before and after orthognathic surgery.

Patients: Nineteen patients were enrolled, 9 males and 10 females, aged 17-34 years. Four patients were suffering from a prognathic syndrome (skeletal class II with mandibular retrusion) and were candidates for surgical correction involving a mandibular Bilateral Sagittal Split Osteotomy (BSSO), whereas the other 15 patients showed a progenic syndrome (skeletal class III with mandibular protrusion) and were selected for bimaxillary surgery with maxillary advancement and mandibular retrusion.