Metabolic Associated Fatty Liver Disease in Children and Adolescents: Mechanisms of a Silent Epidemic and Therapeutic Options.

Non-alcoholic fatty liver disease (NAFLD) is now identified as a hepatic sign of metabolic syndrome and is the most frequent cause of chronic liver disease in all ages. It is assumed that a genetic predisposition associated with epigenetic factors participates in the evolution of this condition. Visceral obesity and insulin resistance (IR) have always been considered the most important causative factors of Metabolic Syndrome (MetS) and NAFLD, but currently, the interaction between genetic heritage and environmental factors is increasingly considered fundamental in the genesis of metabolic disorders associated with NAFLD. In fact, in patients with NAFLD, insulin resistance, arterial hypertension, abdominal obesity, dyslipidemia and reduced intestinal permeability have often been found, as well as a higher prevalence of coronary artery disease, obstructive sleep apnea, polycystic ovary syndrome and osteopenia, which define a MetS framework. Early diagnosis is needed to prevent disease progression through primarily lifestyle interventions. Unfortunately, at present, there are no molecules recommended for pediatric patients. However, several new drugs are in clinical trials. For this reason, targeted studies on the interaction between genetics and environmental factors involved in the development of NAFLD and MetS and on the pathogenetic mechanisms that determine the evolution in non-alcoholic steatohepatitis (NASH), should be implemented. Therefore, it is desirable that future studies may be useful in identifying patients at risk of developing NAFLD and MetS early.

The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Haploinsufficiency in SON may affect multiple genes, including those involved in the development and metabolism of multiple organs. Considering the broad spectrum of SON functions, it is to be expected that pathogenic variants in this gene can cause a wide spectrum of clinical symptoms. We present an additional ZTTK syndrome case due to a de novo heterozygous variant in the SON gene (c.5751_5754delAGTT). The clinical manifestations of our patient were similar to those present in previously reported cases; however, the diagnosis of ZTTK syndrome was delayed for a long time and was carried out during the diagnostic work-up of significant chronic liver disease (CLD). CLD has not yet been reported in any series; therefore, our report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement. Correspondingly, we recommend screening patients with SON variants specifically for liver involvement from the first years of life. Once the CLD has been diagnosed, an appropriate follow-up is mandatory, especially considering the role of SON as an emerging player in cancer development. Further studies are needed to investigate the role of SON haploinsufficiency as a downregulator of essential genes, thus potentially impairing the normal development and/or functions of multiple organs.

The Role of the GH/IGF1 Axis on the Development of MAFLD in Pediatric Patients with Obesity.

The anomalies of the Growth Hormone (GH)/Insulin-like Growth Factor-1 (IGF1) axis are associated with a higher prevalence of Metabolic Associated Fatty Liver Disease (MAFLD) and with a more rapid progression towards fibrosis, cirrhosis, and end-stage liver disease. A total of 191 adolescents with obesity [12−18 years] were consecutively enrolled between January 2014 and December 2020 and underwent liver biopsy to diagnose MAFLD severity. In all patients GH, IGF1 and Insulin-like Growth Factor-Binding Protein 3 (IGFBP3) were measured. Patients with inflammation and ballooning have significantly lower values of GH and IGF1 than those without (GH: 5.4 vs. 7.5 ng/mL; IGF1 245 vs. 284 ng/mL, p < 0.05). GH and IGF1 were also negatively correlated with fibrosis' degree (r = −0.51, p = 0.001, and r = −0.45, p = 0.001, respectively). Only GH correlated with TNF-a (r = −0.29, p = 0.04) and lobular inflammation (r = −0.36, p = 0.02). At multivariate regression, both GH and IGF1 values, after adjustment for age, sex and BMI, were negatively associated with HOMA-IR but above all with fibrosis (GHâ†’ß = −2.3, p = 0.001, IGF1â†’ß = −2.8, p = 0.001). Even in the pediatric population, a reduction of GH input in the liver directly promotes development of de novo hepatic lipogenesis, steatosis, fibrosis and inflammation. The possible role of recombinant GH administration in adolescents with obesity and severe MAFLD deserves to be studied.

Non-Invasive Diagnostic Test for Advanced Fibrosis in Adolescents With Non-Alcoholic Fatty Liver Disease.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a multifaceted disease that includes a wide spectrum of liver damage. The presence and the degree of fibrosis are considered important factors for the prognosis of NAFLD and in predicting the risk of developing cirrhosis. Our aim was to evaluate the usefulness of four fibrosis scores (aspartate aminotransferase/Platelet Index [APRI], FIB-4, NAFLD Fibrosis Score [NFS], and Hepamet) in predicting different degrees of fibrosis among children with biopsy-proven NAFLD. Methods: About 286 adolescents [mean age 14.3 years ± 2.5; 154 (53.6%) males], referred between January 2014 and December 2019, with biopsy-proven NAFLD were enrolled. Results: About 173 (60.4%) patients presented fibrosis at histological analysis. In particular: 140 (49.3%) patients had F = 1, 31 (10.8%), had F = 2 and 2 (0.66%) had F = 3. APRI (AUROC 0.619, 95% CI 0.556-0.679) and Hepamet (AUROC 0.778, 95% CI 0.722-0.828) scores had significant (p < 0.001) accuracy to distinguish subjects with fibrosis; while NFS and FIB-4 had not. APRI had a positive predictive value (PPV) of 62.77% (95% CI 57.96-67.35) and an negative predictive value (NPV) of 52.01% (95% CI 46.54-57.43); Hepamet a PPV of 63.24% (95% CI 59.95-66.41) and an NPV of 61.29% (52.9-69.01). Conclusions: Our study showed that Hepamet and APRI perform better than NFS and FIB-4 for identifying fibrosis in patients with NAFLD, but do not have PPVs so high to be considered diagnostic. Therefore, they cannot be employed, in children, for a certain diagnosis of fibrosis or its progression and cannot replace liver biopsy as the gold diagnostic standard. It is, therefore, necessary to continue to research and develop new markers of exclusive fibrosis.

Angular-Resolved Thomson Parabola Spectrometer for Laser-Driven Ion Accelerators.

This article reports the development, construction, and experimental test of an angle-resolved Thomson parabola (TP) spectrometer for laser-accelerated multi-MeV ion beams in order to distinguish between ionic species with different charge-to-mass ratio. High repetition rate (HHR) compatibility is guaranteed by the use of a microchannel plate (MCP) as active particle detector. The angular resolving power, which is achieved due to an array of entrance pinholes, can be simply adjusted by modifying the geometry of the experiment and/or the pinhole array itself. The analysis procedure allows for different ion traces to cross on the detector plane, which greatly enhances the flexibility and capabilities of the detector. A full characterization of the TP magnetic field is implemented into a relativistic code developed for the trajectory calculation of each pinhole beamlet. We describe the first test of the spectrometer at the 1PW VEGA 3 laser facility at CLPU, Salamanca (Spain), where up to 15MeV protons and carbon ions from a 3µm laser-irradiated Al foil are detected.

Control of the Two-photon Visual Process in ex vivo Retinas and in Living Mice.

Palcewska et al. first demonstrated near infrared (NIR) visual response in human volunteers upon two-photon absorption (TPA), in a seminal work of 2014, and assessed the process in terms of wavelength- and power-dependence on murine ex-vivo retinas. In the present study, ex-vivo electroretinography (ERG) is further developed to perform a complete characterization of the effect of NIR pulse duration, energy, and focal spot size on the response. The same set of measurements is successively tested on living mice. We discuss how the nonlinear intensity dependence of the photon absorption process is transferred to the amplitude of the visual response acquired by ERG. Finally, we show that the manipulation of the spectral phase of NIR pulses can be translated to predictable change in the two-photon induced response under physiological excitation conditions.

Multiorder Nonlinear Mixing in Metal Oxide Nanoparticles.

Whereas most of the reports on the nonlinear properties of micro- and nanostructures address the generation of distinct signals, such as second or third harmonic, here we demonstrate that the novel generation of dual output lasers recently developed for microscopy can readily increase the accessible parameter space and enable the simultaneous excitation and detection of multiple emission orders such as several harmonics and signals stemming from various sum and difference frequency mixing processes. This rich response, which in our case features 10 distinct emissions and encompasses the whole spectral range from the deep ultraviolet to the short-wave infrared region, is demonstrated using various nonlinear oxide nanomaterials while being characterized and simulated temporally and spectrally. Notably, we show that the response is conserved when the particles are embedded in biological media opening the way to novel biolabeling and phototriggering strategies.

Multimode single-pass spatio-temporal squeezing.

We present a single-pass source of broadband multimode squeezed light with potential application in quantum information and quantum metrology. The source is based on a type I parametric down-conversion (PDC) process inside a bulk nonlinear crystal in a non-collinear configuration. The generated squeezed light exhibits a spatio-temporal multimode behavior that is probed using a homodyne measurement with a local oscillator shaped both spatially and temporally. Finally we follow a covariance matrix based approach to reveal the distribution of the squeezing among several independent temporal and spatial modes. This unambiguously validates the multimode feature of our source.

Off-axis spiral phase mirrors for generating high-intensity optical vortices.

In this work, we present a novel, to the best of our knowledge, and practical method for generating optical vortices in high-power laser systems. Off-axis spiral phase mirrors are used at oblique angles of incidence in the beam path after amplification and compression, allowing for the generation of high-power optical vortices in almost any laser system. An off-axis configuration is possible via modification of the azimuthal gradient of the spiral phase helix and is demonstrated with a simple model using a discrete spiral staircase. This work presents the design, fabrication, and implementation of off-axis spiral phase mirrors in both low- and high-power laser systems.

Characterisation and Modelling of Ultrashort Laser-Driven Electromagnetic Pulses.

Recent advances on laser technology have enabled the generation of ultrashort (fs) high power (PW) laser systems. For such large scale laser facilities there is an imperative demand for high repetition rate operation in symbiosis with beamlines or end-stations. In such extreme conditions the generation of electromagnetic pulses (EMP) during high intense laser target interaction experiments can tip the scale for the good outcome of the campaign. The EMP effects are several including interference with diagnostic devices and actuators as well as damage of electrical components. The EMP issue is quite known in the picosecond (ps) pulse laser experiments but no systematic study on EMP issues at multi-Joule fs-class lasers has been conducted thus far. In this paper we report the first experimental campaign for EMP-measurements performed at the 200 TW laser system (VEGA 2) at CLPU laser center. EMP pulse energy has been measured as a function of the laser intensity and energy together with other relevant quantities such as (i) the charge of the laser-driven protons and their maximum energy, as well as (ii) the X-ray Kα emission coming from electron interaction inside the target. Analysis of experimental results demonstrate (and confirm) a direct correlation between the measured EMP pulse energy and the laser parameters such as laser intensity and laser energy in the ultrashort pulse duration regime. Numerical FEM (Finite Element Method) simulations of the EMP generated by the target holder system have been performed and the simulations results are shown to be in good agreement with the experimental ones.

Enhanced relativistic-electron beam collimation using two consecutive laser pulses.

The double laser pulse approach to relativistic electron beam (REB) collimation in solid targets has been investigated at the LULI-ELFIE facility. In this scheme two collinear laser pulses are focused onto a solid target with a given intensity ratio and time delay to generate REBs. The magnetic field generated by the first laser-driven REB is used to guide the REB generated by a second delayed laser pulse. We show how electron beam collimation can be controlled by properly adjusting the ratio of focus size and the delay time between the two pulses. We found that the maximum of electron beam collimation is clearly dependent on the laser focal spot size ratio and related to the magnetic field dynamics. Cu-Kα and CTR imaging diagnostics were implemented to evaluate the collimation effects on the respectively low energy (≤100 keV) and high energy (≥MeV) components of the REB.

A promising medium-term follow-up of pediatric sclerosing cholangitis: Mild phenotype or early diagnosis?

AIM: Sclerosing cholangitis (SC) is a chronic cholestatic liver disease that is being increasingly diagnosed in childhood. The long-term course and prognosis of pediatric SC are poorly described. METHODS: We reviewed data of pediatric SC patients, followed in two referral centers, during a period of up to 20 years. We aimed to evaluate long-term outcomes according to SC phenotype. RESULTS: Among 45 patients (median age, 10.4 years; male patients, 73.4%) 29 (64.4%) were asymptomatic at presentation. Twenty patients (44%) had a concomitant inflammatory bowel disease (SC/IBD). Autoimmune features were found in 20 patients (44%). Liver biopsy showed severe fibrosis or cirrhosis in 32% of cases. Patients with SC alone had a higher rate of interface hepatitis at liver biopsy than SC/IBD patients. All children received ursodeoxycholic acid at diagnosis, and 17 received steroids and/or azathioprine. After a mean follow-up of 8.7 ± 5.6 years, all patients were alive and seven developed at least one liver-related complication. At the end of follow-up, 10 patients stopped immunosuppressants and two had no therapy. Only two patients underwent liver transplantation. Complication-free survival did not differ between SC/IBD and SC patients, but survival was longer in patients without autoimmune features. CONCLUSIONS: In our early diagnosed cohort, the 9-year survival with native liver was better than that reported in other studies. Approximately 15% of patients developed liver-related disease complications, less than previously reported. The long-term course of SC was negatively influenced by the presence of autoimmune features, but not by concomitant IBD.