Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results

\ua9 2024 by American Society of Clinical Oncology. PURPOSE The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial. METHODS The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned. RESULTS The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, -0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSION This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

Metabolic syndrome: a child is not a small adult.

Obesity is associated with an increased all-cause mortality rate and even small weight losses can be associated with short-term reduction in risk factors for disease. There is strong evidence that weight loss in obese subjects improves risk factors for diabetes and cardiaovascular diseases. Metabolic syndrome (MS) in adults is defined as a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which includes abdominal obesity, dyslipidemia, glucose intolerance and hypertension. Application of the MS concept in children and adolescents is controversial; in fact no consensus exists on a specific definition for pediatric MS. Lack of consensus is in part due to body evolution associated with childhood and puberty that is related to changes in metabolic and clinical characteristics. The aim of this article is to try to clarify the differences between the MS as a concept and the MS as a diagnostic category, as well as to develop a theory related to its pathophysiology. We comment on the relationship between obesity, regional fat distribution and the MS, and finally we offer some insights into MS methodological approaches for estimating metabolic risk-factor clustering in children and adolescents

Growth: healthy status and active food model in pediatrics.

OBJECTIVE: The brain integrates peripheral signals of nutrition in order to maintain a stable body weight. Nutritional status defined as the results of introduction, absorption, and utilization of the nutrients could be interpreted with the base of the relationship between nutritional status and healthy status. In this view, energy balance, body function, and body composition are three entities correlated to each other to the healthy status. AIM: To discuss the nutritional status in relation with healthy status, and its relationship with growth and nutrients. METHODS: A review of the available literature on food patterns and active food model was carried out. RESULTS: In the reviewed studies, strategies that could offer promising results to prevent overweight and obesity were discussed, in particular in the light of functional foods that effect energy metabolism and fat partitioning. CONCLUSION: At this moment it is necessary to proactively discuss and promote healthy eating behaviors among children at an early age and empower parents to promote children's ability to self-regulate energy intake while providing appropriate structure and boundaries around eating

Healthy status and energy balance in pediatrics.

During growth, the human body increases in size and changes proportion of various components due to hormones mediators. Nutritional status is the result of introduction, absorption and utilization of the nutrients and it has a new definition in the relationship between nutritional status and healthy status. In this view energy balance, body function and body composition are three entities correlated each other. This mini-review article examines issues and techniques specifically related to a pediatric population in the field of body composition and energy expenditure. It is broadly divided into two sections. The first section discusses body composition measurements underlying principles, advantages, disadvantages and consensus. The second section reviews energy expenditure and physical activity measurement techniques. In conclusion general clinical suggestions are offered regarding pediatric body composition, healthy status and energy balance

Effect of intense military training on body composition

Individuals in a structural physical training program can show beneficial changes in body composition, such as body fat reduction and muscle mass increase. This study measured body composition changes by using 3 different techniques-skinfold thickness (SF) measurements, air displacement plethysmography (BOD-POD), and dual-energy x-ray absorptiometry (DXA)-during 9 months of intense training in healthy young men engaged in military training. Twenty-seven young men were recruited from a special faction of the Italian Navy. The program previewed three phases: ground combat, sea combat, and amphibious combat. Body composition was estimated at the beginning, in the middle, and at the end of the training. After the subjects performed the ground combat phase, body composition variables significantly decreased: body weight (P < 0.05), fat-free mass (FFM) (P < 0.001), and fat mass (FM) (P < 0.03). During the amphibious combat phase, body weight increased significantly (P < 0.01), mainly because of an increase in FFM (P < 0.001) and a smaller mean decrease in FM. There was a significant difference (P < 0.05) in circumferences and SF at various sites after starting the training course. Bland-Altman analysis did not show any systematic difference between FM and FFM measured with the 3 different techniques on any occasion. On any visit, FFM and FM correlation measured by BOD-POD (P = 0.90) and DXA was significantly greater than measured by SF. A significant difference was found in body mass index (BMI) measured during the study. BOD-POD and SF, compared with DXA, provide valid and reliable measurement of changes in body composition in healthy young men engaged in military training. In conclusion, the findings suggest that for young men of normal weight, changes in body weight alone and in BMI are not a good measure to assess the effectiveness of intense physical training programs, because lean mass gain can masquerade fat weight loss

A new device for measuring resting energy expenditure (REE) in healthy subjects.

BACKGROUND AND AIM: Lifestyle change targeted towards increasing daily resting energy expenditure (REE) is one of the cornerstones of obesity treatment. Measurements of energy expenditure and substrate utilization are essential to understanding the metabolic basis of obesity, and the physiological responses to perturbations in habitual food intake. REE is the largest part of human energy expenditure (60-70%) and an increase or decrease in REE would have a large impact on total energy. Accurate and easy-to-use methods for measuring REE are needed, to be applied by clinicians in daily clinical settings to assess the validity of a new instrument to estimate REE in normal weight, healthy adults. METHODS: Ninety-nine subjects (52 females and 47 males) (mean+/-SD, age 38+/-14 years; body mass index (BMI) 23+/-3 kg/m(2)) were tested. REE was assessed using a Sensor Medics Vmax metabolic cart with a ventilated canopy and with the SenseWear armband. Body composition, percentage fat mass (%FM) and percentage fat free mass (%FFM) were assessed by skinfold thickness measurements (SF), bio-electrical impedance analysis (BIA) and air displacement plethysmography (BOD-POD). RESULTS: No significant difference was found among measurements of FFM using the three different techniques. Both SenseWear and Sensor Medics Vmax showed a high correlation, r=0.42 and r=0.40 (p<0.0001) respectively, with BMI. No significant difference was found in mean REE between SenseWear (1540+/-280 kcal/day) and Sensor Medics Vmax (1700+/-330 kcal/day) (p=ns) and the correlation between REE measured by SenseWear and Sensor Medics Vmax was high (r=0.86, p<0.0001). Bland-Altman plot showed no difference in REE determination between SenseWear and Sensor Medics Vmax. %FFM determined by BOD-POD correlated with SenseWear (r=0.42, p<0.0001) as well as Sensor Medics Vmax (r=0.38, p<0.001). CONCLUSION: SF, BIA and BOD-POD provide valid and reliable measurements of FFM. Our results suggest that the SenseWear armband is an acceptable device to accurately measure REE in healthy subjects. Its characteristics have the potential to reduce measurement times and make the SenseWear armband useful for epidemiological studies

Resting energy expenditure assessment in anorexia nervosa: comparison of indirect calorimetry, a multisensor monitor and the M\ufcller equation.

The aim of this study was to compare the estimations provided by three different means of measuring the resting energy expenditure (REE) in anorexia nervosa (AN) patients. REE was measured, after 24 h of refeeding, using a portable multisensor body monitor [SenseWear Pro2 Armband (SWA)], FitMate\u2122 method and the M\ufcller equation for individuals with body mass index < 18.5, the latter being based on dual-energy X-ray absorptiometry assessment of body composition. The mean differences between REE values estimated by SWA and those provided by the M\ufcller equation and the FitMate\u2122 method were significantly different from zero in both cases. In contrast, the mean differences between FitMate\u2122 method and M\ufcller equation were weakly significantly different from zero, and a significant correlation was noted between these two methods. In conclusion, the SWA does not appear to be an alternative to FitMate\u2122 and M\ufcller equation methods for assessing REE in AN patients