Anti-staphylococcal activity of a polyphenol-rich citrus extract: synergy with ß-lactams and low proficiency to induce resistance.

Introduction: Antibiotic resistance represents one of the most significant threats to public health in the 21st century. Polyphenols, natural molecules with antibacterial activity produced by plants, are being considered as alternative antimicrobial strategies to manage infections caused by drug-resistant bacteria. In this study, we investigated the antibacterial activity of a polyphenol mixture extracted from citrus fruits, against both antibiotic-susceptible and resistant strains of Staphylococcus aureus and Staphylococcus epidermidis. Methods: Broth microdilution and time-kill curve experiments were used to test the extract anti-staphylococcal activity. Cytotoxicity was assessed by the hemolysis assay. The interaction between the mixture and antibiotics was investigated by the checkerboard assay. The effect of B alone and in combination with oxacillin on the membrane potential was investigated by the 3,3'-dipropylthiadicarbocyanine iodide assay. The ability of the extract to induce the development of resistance was verified by propagating S. aureus for 10 transfers in the presence of sub-inhibitory concentrations. Results: The citrus extract was found to be active against all Staphylococcus strains at remarkably low concentrations (0.0031 and 0.0063%), displaying rapid bactericidal effects without being toxic on erythrocytes. In particular, B was found to rapidly cause membrane depolarization. When combined with methicillin, meropenem, and oxacillin, the mixture displayed synergistic activity exclusively against methicillin-resistant strains. We additionally show that the sequential exposure of S. aureus to sub-inhibitory concentrations did not induce the development of resistance against the extract. Discussion: Overall, these findings support the potential use of the citrus extract as promising option to manage staphylococcal infections and suggest that it may counteract the mechanism behind methicillin-resistance.

Dissecting the role of the MS-ring protein FliF in Bacillus cereus flagella-related functions.

The flagellar MS-ring, uniquely constituted by FliF, is essential for flagellar biogenesis and functionality in several bacteria. The aim of this study was to dissect the role of FliF in the Gram-positive and peritrichously flagellated Bacillus cereus. We demonstrate that fliF forms an operon with the upstream gene fliE. In silico analysis of B. cereus ATCC 14579 FliF identifies functional domains and amino acid residues that are essential for protein functioning. The analysis of a ΔfliF mutant of B. cereus, constructed in this study using an in frame markerless gene replacement method, reveals that the mutant is unexpectedly able to assemble flagella, although in reduced amounts compared to the parental strain. Nevertheless, motility is completely abolished by fliF deletion. FliF deprivation causes the production of submerged biofilms and affects the ability of B. cereus to adhere to gastrointestinal mucins. We additionally show that the fliF deletion does not compromise the secretion of the three components of hemolysin BL, a toxin secreted through the flagellar type III secretion system. Overall, our findings highlight the important role of B. cereus FliF in flagella-related functions, being the protein required for complete flagellation, motility, mucin adhesion, and pellicle biofilms.

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Neutrophil-to-Eosinophil Ratio Predicts the Efficacy of Avelumab in Patients With Advanced Urothelial Carcinoma Enrolled in the MALVA Study (Meet-URO 25).

BACKGROUND: Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb ([MALVA] in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25). PATIENTS AND METHODS: Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported. RESULTS: At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (

Anti-Staphylococcal Biofilm Effects of a Liposome-Based Formulation Containing Citrus Polyphenols.

Biofilms are surface-associated microbial communities embedded in a matrix that is almost impenetrable to antibiotics, thus constituting a critical health threat. Biofilm formation on the cornea or ocular devices can lead to serious and difficult-to-treat infections. Nowadays, natural molecules with antimicrobial activity and liposome-based delivery systems are proposed as anti-biofilm candidates. In this study, the anti-biofilm activity of a formulation containing citrus polyphenols encapsulated in liposomes was evaluated against Staphylococcus aureus and Staphylococcus epidermidis, the most common agents in ocular infections. The formulation activity against planktonic staphylococci was tested by broth microdilution and sub-inhibitory concentrations were used to evaluate the effect on biofilm formation using the crystal violet (CV) assay. The eradicating effect of the preparation on mature biofilms was investigated by the CV assay, plate count, and confocal laser scanning microscopy. The product was bactericidal against staphylococci at a dilution of 1:2 or 1:4 and able to reduce biofilm formation even if diluted at 1:64. The formulation also had the ability to reduce the biomass of mature biofilms without affecting the number of cells, suggesting activity on the extracellular matrix. Overall, our results support the application of the used liposome-encapsulated polyphenols as an anti-biofilm strategy to counter biofilm-associated ocular infections.

Wastewater-Based Epidemiology for Viral Surveillance from an Endemic Perspective: Evidence and Challenges.

Wastewater-based epidemiology (WBE) is currently used to monitor not only the spread of the viral SARS-CoV-2 pandemic but also that of other viruses in endemic conditions, particularly in the absence of syndromic surveillance. The continuous monitoring of sewage requires high expenditure and significant time investments, highlighting the need for standardized methods and structured monitoring strategies. In this context, we conducted weekly wastewater monitoring in northwestern Tuscany (Italy) and targeted human adenovirus (HAdV), norovirus genogroup II (NoVggII), enterovirus (EV), and SARS-CoV-2. Samples were collected at the entrances of treatment plants and concentrated using PEG/NaCl precipitation, and viral nucleic acids were extracted and detected through real-time reverse transcription qPCR. NoVggII was the most identified target (84.4%), followed by HAdV, SARS-CoV-2, and EV. Only HAdV and EV exhibited seasonal peaks in spring and summer. Compared with data that were previously collected in the same study area (from February 2021 to September 2021), the results for SARS-CoV-2 revealed a shift from an epidemic to an endemic pattern, at least in the region under investigation, which was likely due to viral mutations that led to the spreading of new variants with increased resistance to summer environmental conditions. In conclusion, using standardized methods and an efficient monitoring strategy, WBE proves valuable for viral surveillance in pandemic and epidemic scenarios, enabling the identification of temporal-local distribution patterns that are useful for making informed public health decisions.

Dietary habits, depression and obesity: an intricate relationship to explore in pediatric preventive strategies.

Obesity and depression represent major health problems due to their high prevalence and morbidity rates. Numerous evidences elucidated the connections between dietary habits and the incidence or severity of depression. This overview aims to investigate the intricate relationship between dietary patterns and depression with the objective of elaborating preventive strategies for childhood obesity. Literature data recognized that there is a link between mood and food choices, with certain foods selected for their impact on the brain's reward centers. This behavior parallels the one observed in substance addiction, suggesting a specific neural mechanism for food addiction that contributes to overeating and obesity. It is important to note the significant correlation between obesity and depression, indicating a shared biological pathway influencing these conditions. Stress substantially affects also eating behaviors, often leading to increased consumption of pleasurable and rewarding foods. This can trigger a cycle of overeating, weight gain, and psychological distress, exacerbating mood disorders and obesity. In addition, consumption of certain types of foods, especially "comfort foods" high in fat and calories, may provide temporary relief from symptoms of depression, but can lead to long-term obesity and further mental health problems. Understanding these complex interactions is critical to developing preventive strategies focusing on dietary, emotional, and environmental factors, thereby reducing the risk of obesity and mood disorders.

Food Intake and Sleep Disorders in Children and Adolescents with Obesity.

Over the last few decades, numerous scientific studies have investigated the possible association between sleep duration and adiposity during childhood, since it has been reported that sleep deprivation causes a related increase in caloric intake. Even though the underlying pathogenetic mechanisms are still under study and not completely known, the effect of dietetic habits and nutrient intake on sleep quality and patterns has been reported. The aim of this study is to explore the intricate interplay between food intake/diet patterns and pediatric sleep disturbances in children and adolescents with obesity, emphasizing the importance of not underestimating this aspect in the prevention and treatment of this complex disease. Recent evidence supports a high correlation between specific diet patterns and foods with sleep disturbances in children at all ages. Diets rich in fiber, fruit, vegetables, and anti-inflammatory nutrients and low in saturated fats seem to promote better sleep quality. Sleep disturbances are, in turn, risk factors for the development of obesity. Therefore, food strategies should be applied to counteract this harmful process. Unraveling the complex links between dietary habits, sleep patterns, and obesity is essential for developing effective strategies to combat this critical public health issue.

Cardiovascular Risk in Pediatrics: A Dynamic Process during the First 1000 Days of Life.

The early childhood period, encompassing prenatal and early stages, assumes a pivotal role in shaping cardiovascular risk factors. We conducted a narrative review, presenting a non-systematic summation and analysis of the available literature, focusing on cardiovascular risk from prenatal development to the first 1000 days of life. Elements such as maternal health, genetic predisposition, inadequate fetal nutrition, and rapid postnatal growth contribute to this risk. Specifically, maternal obesity and antibiotic use during pregnancy can influence transgenerational risk factors. Conditions at birth, such as fetal growth restriction and low birth weight, set the stage for potential cardiovascular challenges. To consider cardiovascular risk in early childhood as a dynamic process is useful when adopting a personalized prevention for future healthcare and providing recommendations for management throughout their journey from infancy to early adulthood. A comprehensive approach is paramount in addressing early childhood cardiovascular risks. By targeting critical periods and implementing preventive strategies, healthcare professionals and policymakers can pave the way for improved cardiovascular outcomes. Investing in children's health during their early years holds the key to alleviating the burden of cardiovascular diseases for future generations.

Breast and Formula Milk and Early Puberty Onset.

Nutrients have an enormous impact on many hormonal systems and aspects of health, and nutrition status is a crucial regulator of growth and pubertal development in children and adolescents. In this narrative review, we explore the connection between these feeding methods and the timing of puberty to provide a clearer understanding of how infant nutrition might contribute to the early development of puberty. Puberty is a key stage in the transition from childhood to adulthood and the timing of puberty represents a significant biological milestone of growth. Breast milk seems to have a pivotal role in puberty onset, mainly due to its dynamism, which shape indirectly the gut microbiota in early life, besides direct exposure of the baby to the milk microbiota through gut-breast axis. Concerning breast and formula milk and their effects on the onset of puberty, a protective role of the former occurs. As for the potential harmful effects of soy-based formulas and the isoflavones that they contain, the studies reported demonstrate conflicting opinions, underlining the need for further research on this topic. A healthy and well-nourished diet from the earliest stages of life has significant preventive potential for overall well-being, reducing the risk of many health problems later in life.

Bone Metastases in Renal Cell Carcinoma: Impact of Immunotherapy on Survival.

Background/Aim: We performed a multicenter retrospective observational study to investigate the impact of immune checkpoint inhibitors (ICIs) on the survival of patients with bone metastases (BMs) from renal cell cancer (RCC). Patients and Methods: A total of 98 patients with metastatic RCC (mRCC) treated with ICIs were retrospectively enrolled. All patients received standard treatments with nivolumab alone or in combination with ipilimumab from December 2015 to March 2022. The primary endpoint was median overall survival (OS). Results: Forty-three patients (44%) had radiological evidence of BMs. No statistically significant difference in OS was reported between the BM population and the entire population (p=0.254). Conclusion: Our study suggests some degree of ICI activity to treat patients with BMs from RCC, historically associated with a poorer prognosis.

Probiotics and Polycystic Ovary Syndrome: A Perspective for Management in Adolescents with Obesity.

Polycystic ovary syndrome (PCOS) affects a considerable percentage of females of reproductive age. PCOS is an obesity-related condition and its effects are greatly amplified by obesity. Even though the pathogenesis of PCOS remains complex and has not been fully elucidated, a link between obesity, PCOS, and dysbiosis has been described. The potential role of the gut microbiota in the development and progression of PCOS and its associated symptoms has also been reported. The aim of this narrative review is to present a non-systematic analysis of the available literature on the topic of probiotics and PCOS in adolescents with obesity in order to revise the beneficial effects of probiotics/symbiotic supplementation on hormonal and metabolic profiles and inflammatory conditions. The effectiveness of probiotics/synbiotics in PCOS has been supported. The literature suggests that probiotic/symbiotic supplementation may ameliorate hormonal profiles, inflammatory indicators, and lipid metabolism disturbances caused by PCOS. Studies also show improvements in weight, BMI, insulin, and HOMA-IR, including a potential role it plays in protecting fertility. Even though further studies are needed to confirm these findings, particularly in adolescent patients, probiotic supplementation may be considered a solution for managing PCOS in adolescents with obesity.

Exergames to Limit Weight Gain and to Fight Sedentarism in Children and Adolescents with Obesity.

Exergames are defined as digital games that require bodily movements to play, stimulating an active gaming experience to function as a form of physical activity (PA). The players interact with the game through whole-body movements improving energy expenditure. Exergames may be effective in improving physical and psychological aspects of children and adolescents with obesity. In this narrative review, we synthesized the current evidence regarding the role of exergames in modifying body composition and weight and in promoting changes in sedentary behavior to define the benefits of active video games as useful tools for fighting sedentarism and to outline the future directions of exergaming as a supplementation exercise rather than a replacement in educational programs for pediatric obesity. Data from the literature indicate that exergames may offer an interesting impact on childhood obesity and may be considered a potential strategy for controlling weight gain and body composition, promote PA, and decrease time spent on sedentary behavior in children and adolescents with obesity. However, exergame use also has some limits, such as children's poor self-regulation and poor structuring of exergame use. Therefore, a prudent approach should be maintained, and additional high-quality research is needed to determine if exergames can be effectively used in the treatment of childhood obesity and if new digital media, as a supplementation of exercise rather than a replacement, could be considered to combat sedentary behavior in educational programs for pediatric obesity prevention.

Ultra-Processed Food, Reward System and Childhood Obesity.

Obesity and overweight are a major public health problem globally. Diet quality is critical for proper child development, and an unhealthy diet is a preventable risk factor for noncommunicable diseases (NCDs), such as obesity. Consumption of sugar-sweetened beverages and ultra-processed foods (UPFs) in childhood may increase the BMI/BMI z-score, body fat percentage, or likelihood of overweight. A strict feeding regulation system allows for sufficient food to be consumed to meet ongoing metabolic demands while avoiding overconsumption. This narrative review explores the issues of obesity and the regulation of food intake related to reward systems and UPF consumption. Nutrient composition alone cannot explain the influence of UPFs on the risk of obesity. Furthermore, the non-nutritional properties of UPFs may explain the mechanisms underlying the relationship with obesity and NCDs. UPFs are designed to be highly palatable, appealing, and energy dense with a unique combination of the main taste enhancer ingredients to generate a strong rewarding stimulus and influence the circuits related to feeding facilitation. How individual UPF ingredients influence eating behavior and reward processes remains not fully elucidated. To increase the knowledge on the relationship between UPFs and pediatric obesity, it may be useful to limit the rapid growth in the prevalence of obesity and subsequent related complications, and to develop new strategies for appropriate food and nutrition policies.

Benefits in Cardiac Function from a Remote Exercise Program in Children with Obesity.

Physical activity (PA) is a crucial factor in preventing and treating obesity and related complications. In this one-arm pre−post longitudinal prospective study, we evaluated the effects of a 12-week online supervised training program on cardiac morphology, function and blood pressure (BP) in children with obesity. The training program consisted of three sessions per week, each lasting 60 min. Advanced echocardiographic imaging (tissue Doppler and longitudinal strain analysis) was used to detect subclinical changes in heart function. Categorical variables were described as counts and percentages; quantitative variables as the mean and standard deviation (SD) as they were normally distributed (Shapiro−Wilks test). Pre−post comparisons were made with a paired t-test. A total of 27/38 (71%) enrolled patients (18M/9F, 11 ± 2 years) completed the training protocol and were considered in the analysis. At baseline, no hypertensive patient was noted; all echocardiographic variables were within the normal range. After training, we observed a significant reduction in BP parameters, including systolic BP values and Z-score, diastolic BP values, centiles and Z-score, and mean arterial pressure (all p < 0.05). Significant variations in echocardiographic interventricular septum (IVSd) thickness (p = 0.011), IVSd Z-score (p = 0.001), left ventricular (LV) end-diastolic diameter (p = 0.045), LV posterior wall thickness Z-score (p = 0.017), and LV global longitudinal strain (p = 0.016) were detected. No differences in LV diastolic function and right ventricular strain were noted. PA plays a decisive role in improving BP control and has benefits on left ventricle systolic function, representing a strategic approach to limit CV risk. Online exercise could be an excellent method of training in children with obesity.

Lipodystrophies in non-insulin-dependent children: Treatment options and results from recombinant human leptin therapy.

Lipodystrophy is a general definition containing different pathologies which, except for those observed in insulin-treated subjects falling outside the scope of this paper, are characterized by total or partial lack of body fat, that, according to the amount of missing adipose tissue, are divided in generalized or partial lipodystrophy. These diseases are characterized by leptin deficiency, which often leads to metabolic derangement, causing insulin resistance, dyslipidemia, and increasing cardiovascular risk. In this narrative review, we presentend the clinical presentation of different types of lipodystrophies and metabolic unbalances related to disease in children and adolescents, focusing on the main treatment options and the novel results from recombinant human leptin (metreleptin) therapy. Milestones in the management of lipodystrophy include lifestyle modification as diet and physical activity, paired with hypoglycemic drugs, insulin, hypolipidemic drugs, and other drugs with the aim of treating lipodystrophy complications. Metreleptin has been recently approved for pediatric patients with general lipodystrophy (GL)> 2 years of age and for children with partial lipodystrophy (PL)> 12 years of age not controlled with conventional therapies. New therapeutic strategies are currently being investigated, especially for patients with PL forms, specifically, liver-targeted therapies. Further studies are needed to achieve the most specific and precise treatment possible.

Childhood Obesity and Incorrect Body Posture: Impact on Physical Activity and the Therapeutic Role of Exercise.

Obesity is associated with various dysfunctions of the organism, including musculoskeletal problems. In this narrative review, we aim to consider postural problems in children and adolescents with obesity, focusing on the relationship with its negative impact on physical activity, and to discuss the role of exercise as a therapeutic approach. The body reacts to excess weight by changing its normal balance, and the somatosensory system of children with obesity is forced to make major adjustments to compensate for postural problems. These adaptations become more difficult and tiring if activities that require continuous postural changes and multi-tasking are engaged in. Children with obesity have less body control and functional ability due to the excess fat mass, which reduces their ability to perform motor skills and take part in physical activity. Appropriate early interventions for the management of musculoskeletal problems are needed to ensure healthy growth and to prevent comorbidities in childhood and adulthood. Prevention programs must be based not only on the reduction of body weight but also on the definition of correct postural habits from an early age. It is equally important to provide correct information on the types and doses of physical activity that can help prevent these problems.

Precocious puberty and microbiota: The role of the sex hormone-gut microbiome axis.

Puberty is a critical phase of life associated with physiological changes related to sexual maturation, and represents a complex process regulated by multiple endocrine and genetic controls. Puberty is driven by hormones, and it can impact the gut microbiome (GM). GM differences between sex emerge at puberty onset, confirming a relationship between microbiota and sex hormones. In this narrative review, we present an overview of precocious pubertal development and the changes in the GM in precocious puberty (PP) in order to consider the role of the sex hormone-gut microbiome axis from the perspective of pediatric endocrinology. Bidirectional interactions between the GM and sex hormones have been proposed in different studies. Although the evidence on the interaction between microbiota and sex hormones remains limited in pediatric patients, the evidence that GM alterations may occur in girls with central precocious puberty (CPP) represents an interesting finding for the prediction and prevention of PP. Deepening the understanding of the connection between the sex hormones and the role of microbiota changes can lead to the implementation of microbiota-targeted therapies in pubertal disorders by offering a pediatric endocrinology perspective.

The Effect of Healthy Lifestyle Strategies on the Management of Insulin Resistance in Children and Adolescents with Obesity: A Narrative Review.

Childhood obesity is characterized by an increased risk of several metabolic derangements including insulin resistance (IR). The strongest recommendations to prevent obesity and related complications are a balanced and adequate diet and practicing physical activity from early childhood. In this review, we propose to present the effects of healthy lifestyle strategies, including physical exercise and dietary approaches, on the management of IR and related metabolic derangements. All types of exercise (aerobic, resistance and combined training) effectively reduce IR in pediatric patients with obesity; it seems that aerobic and combined training stimulate greater improvements in IR compared to resistance training. Balanced normocaloric or hypocaloric dietary approaches are also valid strategies to address IR; it is not possible to assess the long-term impact of varying macronutrients on cardiometabolic risk. The glycemic index/load evaluation is a useful dietary approach to glucose metabolism control. Similarly, they should adopt the principle of the Mediterranean diet. Randomized studies with longer monitoring are needed to define the benefits of nutritional supplementation on IR. Considering that healthy style acquisition could track to later ages, programs of healthy lifestyle starting with children offer a better preventive strategy to preserve metabolic control and children's health.