The face of Glut1-DS patients : A 3D craniofacial morphometric analysis

Introduction - Glut1 deficiency syndrome (Glut1-DS) is a neurological and metabolic disorder caused by impaired transport of glucose across the blood brain barrier (BBB). Mutations on the SCL2A1 gene encoding the glucose transporter protein in the BBB cause the syndrome, which encompasses epilepsy, movement disorders and mental delay. Such variability of symptoms presents an obstacle to early diagnosis. The patients seem to share some craniofacial features, and identification and quantification of these could help in prompt diagnosis and clinical management. Materials and method - We performed a three-dimensional morphometric analysis of the faces of 11 female Glut1-DS patients using a stereophotogrammetric system. Data were analyzed using both inter-landmark distances and Principal Component Analysis (PCA). Results - Compared to data collected from age-, sex- and ethnicity-matched control subjects, common and homogenous facial features were identified among patients, which were mainly located in the mandible and the eyes. Glut1-DS patients had a more anterior chin; their mandibular body was longer but the rami were shorter, with a reduced gonial angle; they had smaller and down-slanted eyes with a reduced intercanthal distance. Conclusions - This study highlights the importance of morphometric analysis for defining the facial anatomical characteristics of the syndrome better, potentially helping clinicians to diagnose Glut1-DS. Imnproved knowledge of the facial anatomy of these patients can provide insights into their facial and cerebral embryological development, perhaps further clarifying the molecular basis of the syndrome

One Month of Classic Therapeutic Ketogenic Diet Decreases Short Chain Fatty Acids Production in Epileptic Patients

Ketogenic diet (KD), a high fat and very low carbohydrates diet, is used worldwide for the treatment of drug resistant epilepsy but, due to its composition, it might exert an impact on gut health. Even though data of KD effects on intestinal microbiota changes are recently emerging, its influence on the gut environment has been scarcely addressed so far. The aim of this study was to investigate whether 1 month of KD affects the gut environment in epileptic patients, by analyzing short chain fatty acids (SCFA) production and fecal water toxicity. A total of seven patients were enrolled. Stool samples were collected before (T0) and after 1 month of KD (4:1 ketogenic ratio) (T1). SCFA were determined by GC-FID and fecal water toxicity in Caco-2 cell culture by comet assay. Concentrations of SCFA significantly decreased after KD (p < 0.05): in particular, we found a 55% reduction of total SCFA level, a 64% reduction of acetate, 33% of propionate, and 20% of butyrate (p < 0.05). Cytotoxicity of fecal water extracted from stool samples was not significantly altered by diet, while genotoxicity was slightly decreased after KD (p < 0.05). Genotoxicity values were consistent with data previously obtained from a healthy Italian population. The present study suggests that 1 month of KD significantly reduce SCFA production. Since SCFA produced by gut microbiota exert many health promoting effects on either the gut environment or human metabolism, these results open a new branch of investigation into KD effects

Effect of mechanical power on intensive care mortality in ARDS patients

Background: In ARDS patients, mechanical ventilation should minimize ventilator-induced lung injury. The mechanical power which is the energy per unit time released to the respiratory system according to the applied tidal volume, PEEP, respiratory rate, and flow should reflect the ventilator-induced lung injury. However, similar levels of mechanical power applied in different lung sizes could be associated to different effects. The aim of this study was to assess the role both of the mechanical power and of the transpulmonary mechanical power, normalized to predicted body weight, respiratory system compliance, lung volume, and amount of aerated tissue on intensive care mortality. Methods: Retrospective analysis of ARDS patients previously enrolled in seven published studies. All patients were sedated, paralyzed, and mechanically ventilated. After 20 min from a recruitment maneuver, partitioned respiratory mechanics measurements and blood gas analyses were performed with a PEEP of 5 cmH2O while the remaining setting was maintained unchanged from the baseline. A whole lung CT scan at 5 cmH2O of PEEP was performed to estimate the lung gas volume and the amount of well-inflated tissue. Univariate and multivariable Poisson regression models with robust standard error were used to calculate risk ratios and 95% confidence intervals of ICU mortality. Results: Two hundred twenty-two ARDS patients were included; 88 (40%) died in ICU. Mechanical power was not different between survivors and non-survivors 14.97 [11.51-18.44] vs. 15.46 [12.33-21.45] J/min and did not affect intensive care mortality. The multivariable robust regression models showed that the mechanical power normalized to well-inflated tissue (RR 2.69 [95% CI 1.10-6.56], p = 0.029) and the mechanical power normalized to respiratory system compliance (RR 1.79 [95% CI 1.16-2.76], p = 0.008) were independently associated with intensive care mortality after adjusting for age, SAPS II, and ARDS severity. Also, transpulmonary mechanical power normalized to respiratory system compliance and to well-inflated tissue significantly increased intensive care mortality (RR 1.74 [1.11-2.70], p = 0.015; RR 3.01 [1.15-7.91], p = 0.025). Conclusions: In our ARDS population, there is not a causal relationship between the mechanical power itself and mortality, while mechanical power normalized to the compliance or to the amount of well-aerated tissue is independently associated to the intensive care mortality. Further studies are needed to confirm this data

One-hour post-load plasma glucose levels associated with decreased insulin sensitivity and secretion and early makers of cardiometabolic risk.

PURPOSE: Obese adults with normal glucose tolerance (NGT) but with 1-hour post-load plasma glucose (1hPG) ≥ 155 mg/dl are at higher risk of developing type 2 diabetes (T2D) and cardiometabolic complications. Little information is available for the pediatric population, where recently, a lower cutoff, 132.5 mg/dl, has been suggested as being more sensitive to identify subjects at risk of T2D. Our aim was to assess whether obese Caucasian youth with 1hPG ≥ 132.5 mg/dl have worse insulin sensitivity and secretion and a worse cardiometabolic profile compared to obese youth with 1hPG < 132.5 mg/dl. METHODS: Medical records of 244 (43% male; age: 11.1 ± 2.7years) overweight/obese children and adolescents, who had undergone an oral glucose tolerance test (OGTT), were retrieved. Anthropometric and biochemical data were collected from the hard copy archive. Indexes of insulin resistance (HOMA-IR), insulin sensitivity (WBISI), and insulin secretion (Insulinogenic Index, Disposition Index) were calculated. RESULTS: Of the 244 records analyzed, 215 fulfilled criteria for NGT and had complete biochemical data. Among NGT patients, 42 (19.5%) showed 1hPG ≥ 132.5 mg/dL (high-NGT), while the remaining had 1hPG < 132.5 mg/dL (low-NGT). The high-NGT group showed a higher male prevalence (59.5 vs 37%), lower Disposition Index (0.54 [0.39-0.71] vs 0.79 [0.47-1.43]), and WBISI (0.24 [0.18-0.35] vs 0.33 [0.23-0.50]) than the low-NGT group. High-NGT subjects also showed a trend towards lower HDL-cholesterol and higher triglycerides/HDL-cholesterol ratio (2.13 [1.49-3.41] vs 1.66 [1.24-2.49]). CONCLUSIONS: In overweight/obese NGT Caucasian youth a 1hPG ≥ 132.5 mg/dL was able to identify those with impaired insulin sensitivity and secretion and a trend towards a worse cardio-metabolic profile, a group likely at risk for future T2D

The assessment of esophageal pressure using different devices : a validation study

BACKGROUND: Although esophageal pressure measurement could help clinicians to improve the ventilatory management of acute respiratory distress syndrome (ARDS) patients, it has been mainly used in clinical research. Aim of this study was to compare the measurements of end-expiratory esophageal pressure, end-expiratory transpulmonary pressure and lung stress by three systems: a dedicated manual device, taken as gold standard, a new automatic system (Optivent) and a bedside equipment, consisting of a mechanical ventilator and a hemodynamic monitor. METHODS: In sedated and paralyzed mechanically ventilated ARDS patients the esophageal pressure was measured at three PEEP levels in random fashion (baseline level, 50% higher and 50% lower). RESULTS: Forty patients were enrolled (BMI 25 [23-28] kg/m2, PaO2/FiO2 187 [137-223] and PEEP 9±3 cmH2O). The mean esophageal pressure measured during an expiratory pause by the dedicated system, the bedside system and Optivent were 10.0±4.2, 10±4 and 9.9±4.0 cmH2O, respectively. The respective bias and limits of agreement between the dedicated system and Optivent and between the dedicated system and the bedside system were as follows: end-expiratory esophageal pressure, 0.2 cmH2O, (-0.4 to 0.9) and -0.1 cmH2O (-1.9 to 1.7); end-expiratory transpulmonary pressure, -0.6 cmH2O (-1.7 to 0.4) and -0.4 cmH2O, (-2.2 to 1.5); lung stress -0.9 cmH2O (-3.0 to 1.1) and -1.5 cmH2O (-4.4 to 1.4). CONCLUSIONS: Both Optivent and the bedside system showed clinically acceptability if compared to the gold standard device. The possibility to apply one of these systems could allow a wider use of esophageal pressure in clinical practice

Characterization of speech and language phenotype in GLUT1DS

Background: To analyze the oral motor, speech and language phenotype in a sample of pediatric patients with GLUT 1 transporter deficiency syndrome (GLUT1DS). Methods: eight Italian-speaking children with GLUT1DS (aged 4.6–15.4 years) in stable treatment with ketogenic diet from a variable time underwent a specific and standardized speech and language assessment battery. Results: All patients showed deficits with different degrees of impairment in multiple speech and language areas. In particular, orofacial praxis, parallel and total movements were the most impaired in the oromotor domain; in the speech domain patients obtained a poor performance in the diadochokinesis rate and in the repetition of words that resulted as severely deficient in seven out of eight patients; in the language domain the most affected abilities were semantic/phonological fluency and receptive grammar. Conclusions: GLUT1DS is associated to different levels of speech and language impairment, which should guide diagnostic and therapeutic intervention. Larger population data are needed to identify more precisely a speech and language profile in GLUT1DS patients

Impact of the inversion time on regional brain perfusion estimation with clinical arterial spin labeling protocols

Objective: Evaluating the impact of the Inversion Time (TI) on regional perfusion estimation in a pediatric cohort using Arterial Spin Labeling (ASL). Materials and methods: Pulsed ASL (PASL) was acquired at 3 T both at TI 1500 ms and 2020 ms from twelve MRI-negative patients (age range 9–17 years). A volume of interest (VOIs) and a voxel-wise approach were employed to evaluate subject-specific TI-dependent Cerebral Blood Flow (CBF) differences, and grey matter CBF Z-score differences. A visual evaluation was also performed. Results: CBF was higher for TI 1500 ms in the proximal territories of the arteries (PTAs) (e.g. insular cortex and basal ganglia — P < 0.01 and P < 0.05 from the VOI analysis, respectively), and for TI 2020 ms in the distal territories of the arteries (DTAs), including the watershed areas (e.g. posterior parietal and occipital cortex — P < 0.001 and P < 0.01 from the VOI analysis, respectively). Similar differences were also evident when analyzing patient-specific CBF Z-scores and at a visual inspection. Conclusions: TI influences ASL perfusion estimates with a region-dependent effect. The presence of intraluminal arterial signal in PTAs and the longer arterial transit time in the DTAs (including watershed areas) may account for the TI-dependent differences. Watershed areas exhibiting a lower perfusion signal at short TIs (~ 1500 ms) should not be misinterpreted as focal hypoperfused areas

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

beta-Galactosylceramidase (GALC) is a lysosomal enzyme involved in sphingolipidmetabolismby removing beta-galactosyl moieties from fi-galactosylceramide and beta-galactosylsphingosine. Previous observations have shown that GALC may exert pro-oncogenic functions in melanoma and Galc silencing, leading to decreased oncogenic activity in murine B16 melanoma cells. The tumor-driving BRAF(V600E) mutation is present in approximately 50% of human melanomas and represents a major therapeutic target. However, such mutation is missing in melanoma B16 cells. Thus, to assess the impact of GALC in human melanoma in a more relevant BRAF-mutated background, we investigated the effect of GALC overexpression on the proteomic landscape of A2058 and A375 human melanoma cells harboring the BRAF(V600E) mutation. The results obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrate that significant differences exist in the protein landscape expressed under identical cell culture conditions by A2058 and A375 human melanoma cells, both harboring the same BRAF(V600E)-activating mutation. GALC overexpression resulted in a stronger impact on the proteomic profile of A375 cells when compared to A2058 cells (261 upregulated and 184 downregulated proteins versus 36 and 14 proteins for the two cell types, respectively). Among them, 25 proteins appeared to be upregulated in both A2058-upGALC and A375-upGALC cells, whereas two proteins were significantly downregulated in both GALC-overexpressing cell types. These proteins appear to be involved in melanoma biology, tumor invasion and metastatic dissemination, tumor immune escape, mitochondrial antioxidant activity, endoplasmic reticulum stress responses, autophagy, and/or apoptosis. Notably, analysis of the expression of the corresponding genes in human skin cutaneous melanoma samples (TCGA, Firehose Legacy) using the cBioPortal for Cancer Genomics platform demonstrated a positive correlation between GALC expression and the expression levels of 14 out of the 27 genes investigated, thus supporting the proteomic findings. Overall, these data indicate for the first time that the expression of the lysosomal sphingolipid-metabolizing enzyme GALC may exert a pro-oncogenic impact on the proteomic landscape in BRAF-mutated human melanoma

Ketogenic diet therapy for epilepsy during pregnancy and lactation: An international survey exploring clinician perspectives

\ua9 2025 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.Objective: Ketogenic diet therapies (KDTs) are increasingly used as a treatment for people with epilepsy of childbearing potential (PWECP) and glucose transporter type 1 deficiency syndrome (Glut1DS). The aim of this study was to collect information on clinical experience with KDT during pregnancy and lactation in these populations. Methods: Between December 2023 and June 2024, an online survey was widely circulated to healthcare professionals (HCPs) working with PWECP and people with Glut1DS of childbearing potential on KDT. The survey explored KDT use during pregnancy and lactation. Only HCPs working with patients who expressed interest in KDT and who were planning to become pregnant or were already pregnant were invited to complete the survey. Results: Thirty-five HCPs had counseled patients about whether to follow KDT during pregnancy. Sixty percent of HCPs did not recommend KDT during pregnancy. Key concerns included a lack of expertise with KDT use during pregnancy, insufficient data on the safety of KDT use during pregnancy, and uncertainty about the impact on fetal development. Among the HCPs (40%) who recommended KDT during pregnancy, there was no consensus regarding the version of KDT or optimal macronutrient composition. Even fewer HCPs (n = 5) had provided counseling on diet adaptation during lactation. Low Glycemic Index Treatment and the modified Atkins diet were most recommended. Blood ketone monitoring was unanimously recommended during lactation. Significance: Based on the survey results, HCPs have variable opinions about the safety, management, ideal diet, and levels of ketosis for people with epilepsy (PWE) and Glut1DS on KDT during pregnancy and lactation. There was consensus about monitoring ketosis levels and ensuring micronutrient supplementation. Patient enrollment in pregnancy registries that capture KDT use is crucial to support future research and expand knowledge about the safety of KDT so HCPs and PWE or Glut1DS can make informed decisions about their treatment. Plain Language Summary: Most healthcare providers (HCPs) did not advise ketogenic diet therapy (KDT) for epilepsy during pregnancy, though some noted exceptions for glucose transporter type 1 deficiency syndrome. Their main concerns were not having enough information about safety for the parent and fetus and their own lack of experience using KDT during pregnancy. The 40% of HCPs who supported the use of KDT during pregnancy stressed the need for personalized care and close monitoring to reduce risks. Few HCPs have used KDT during lactation. Experts advised using more flexible versions of KDT during lactation. More research is needed

Intravenous methylprednisolone pulse therapy for children with epileptic encephalopathy

The aim of this retrospective study of children affected by epileptic encephalopathy was to evaluate seizure frequency, electroencephalographic pattern and neuropsychological status, before and after intravenous methylprednisolone therapy. Eleven children with epileptic encephalopathy were administered one cycle of intravenous methylprednisolone (15-30 mg/kg/day for three consecutive days, once a month for four months) in addition to constant dosages of their regular antiepileptic drugs. The treatment resulted in statistically significant reductions of generalized slow spike-and-wave discharges (p<0.0028) and seizure frequency (p<0.013), which persisted even after methylprednisolone pulse therapy was stopped. A globally positive outcome was noted in 9/11 patients (81.8%). This methylprednisolone treatment regimen did not cause significant or persistent adverse effects. We suggest that children with epileptic encephalopathy without an underlying structural lesion could be the best candidates for intravenous methylprednisolone pulse therapy