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Background/Objectives: Chronic inflammatory diseases (CIDs) often present a preclinical phase influenced by genetic and environmental factors, including nutrition. Early dietary habits may modulate long-term health trajectories by shaping the intestinal microbiota. Previous work showed that weaning with fresh foods from the Mediterranean diet (MD) improved dietary habits and microbiota composition at 3 years of age. This study aimed to assess whether such benefits persist at 9 years. Methods: This long-term follow-up included 191 children (96 MD, 95 controls) from the original randomized cohort (ClinicalTrials.gov NCT05297357). The primary endpoint was adherence to MD (KidMed score ≥ 8). Secondary endpoints included BMI, incidence of CID, maternal dietary adherence, and intestinal microbiota composition in a subset of 36 children. Results: At 9 years, no difference was found in overall MD adherence (27.4% controls vs. 27.1% MD; p > 0.99) or BMI (17.7 vs. 18.1 kg/m2; p = 0.384). However, children from the MD group reported higher daily vegetable intake (71.9% vs. 51.6%; p = 0.005). Microbiota analyses revealed persistent differences between groups, with higher alpha diversity in the MD group. Although not statistically significant, the MD group showed lower prevalence of atopic dermatitis, allergic rhinitis, autism spectrum disorder, and ADHD. Maternal adherence to MD did not differ between groups. Conclusions: Early introduction of Mediterranean-style foods during weaning exerts lasting effects on dietary patterns and gut microbiota, with a potential protective trend against CID. While overall MD adherence converged between groups by 9 years, these findings suggest that early-life nutritional interventions may induce durable microbiome-mediated benefits and contribute to preventive strategies for chronic disease, warranting confirmation in larger, extended cohorts. Moreover, this study highlights the value of the collaboration between the Italian primary care pediatric system and the integration of the pediatric residency program, demonstrating a feasible and cost-effective methodology to generate large-scale prospective data within routine clinical practice. Larger studies and a longer follow-up period are necessary to confirm these results.

In Italy, from January 2021, the Ministry of Health indicated a vaccination plan against COVID for frail patients and physicians based on a three-dose scheme. However, conflicting results have been reported on which biomarkers permit immunization assessment. We used several laboratory approaches (i.e., antibodies serum levels, flow cytometry analysis, and cytokines release by stimulated cells) to investigate the immune response in a cohort of 53 family pediatricians (FPs) at different times after the vaccine. We observed that the BNT162b2-mRNA vaccine induced a significant increase of specific antibodies after the third (booster) dose; however, the antibody titer was not predictive of the risk of developing the infection in the six months following the booster dose. The antigen stimulation of PBMC cells from subjects vaccinated with the third booster jab induced the increase of the activated T cells (i.e., CD4+ CD154+); the frequency of CD4+ CD154+ TNF-α+ cells, as well as the TNF-α secretion, was not modified, while we observed a trend of increase of IFN-γ secretion. Interestingly, the level of CD8+ IFN-γ+ (independently from antibody titer) was significantly increased after the third dose and predicts the risk of developing the infection in the six months following the booster jab. Such results may impact also other virus vaccinations.

Mediterranean Diet (Med Diet) is one of the healthiest dietary patterns. We aimed to verify the effects of weaning (i.e., the introduction of solid foods in infants previously fed only with milk) using adult foods typical of Med Diet on children eating habits, and on the microbiota composition. A randomized controlled clinical trial on 394 healthy infants randomized in a 1:1 ratio in a Med Diet group weaned with fresh; seasonal and tasty foods of Med Diet and control group predominantly weaned with industrial baby foods. The primary end point was the percentage of children showing a good adherence to Med Diet at 36 months. Secondary end points were mother’s changes in adherence to Med Diet and differences in children gut microbiota. At 36 months, children showing a good adherence to Med Diet were 59.3% in the Med Diet group and 34.3% in the control group (p < 0.001). An increase in adherence to the Med Diet was observed in the mothers of the Med Diet group children (p < 0.001). At 4 years of age children in the Med Diet group had a higher gut microbial diversity and a higher abundance of beneficial taxa. A Mediterranean weaning with adult food may become a strategy for early nutritional education, to develop a healthy microbiota, to prevent inflammatory chronic diseases and to ameliorate eating habits in children and their families.

The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine β‐synthase (CBS). Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine. Ninety‐two different disease‐associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine‐responsive I278T and the pyridoxine‐nonresponsive G307S. Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene. Hum Mutat 13:362–375, 1999. © 1999 Wiley‐Liss, Inc.

Homocystinuria due to cystathionine β‐synthase (CBS) deficiency is frequently caused by missense mutations. In this article, we report four novel missense mutations in the CBS gene: 172C→T (R58W) linked in cis with A114V; 376A→G (M126V); 904G→A (E302K); and 1006C→T (R336C). The CBS activity of the corresponding mutant enzymes expressed in Escherichia coli was greatly diminished, confirming the pathogenicity of these mutations. Western analysis showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli, while the E302K subunits were partially degraded to shorter products. Using site‐directed mutagenesis we found that CBS containing either the R58W or A114V as the only mutations demonstrated 18% and 46% of normal activity, respectively. Both mutant forms of CBS were stable in E. coli. When these two mutations were expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a control. All these in vitro results were in good agreement with the clinical manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria, while another Italian patient 2242, with an A114V/E302K genotype, responded to pyridoxine treatment and had a much milder phenotype. The third patient 3064, an English compound heterozygote for two severe mutations R336C and G307S, was B6 nonresponsive. This report of a ninth homocystinuric allele carrying two mutations in cis raises the possibility that double mutant alleles may be underestimated in homocystinuric patients. In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype‐phenotype relationship. Hum Mutat 13:453–457, 1999. © 1999 Wiley‐Liss, Inc.

Homocystinuria due to cystathionine ²-synthase (CBS) deficiency is frequently caused by missense mutations. In this article, we report four novel missense mutations in the CBS gene: 172C[arrow right]T (R58W) linked in cis with A114V; 376A[arrow right]G (M126V); 904G[arrow right]A (E302K); and 1006C[arrow right]T (R336C). The CBS activity of the corresponding mutant enzymes expressed in Escherichia coli was greatly diminished, confirming the pathogenicity of these mutations. Western analysis showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli, while the E302K subunits were partially degraded to shorter products. Using site-directed mutagenesis we found that CBS containing either the R58W or A114V as the only mutations demonstrated 18% and 46% of normal activity, respectively. Both mutant forms of CBS were stable in E. coli. When these two mutations were expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a control. All these in vitro results were in good agreement with the clinical manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria, while another Italian patient 2242, with an A114V/E302K genotype, responded to pyridoxine treatment and had a much milder phenotype. The third patient 3064, an English compound heterozygote for two severe mutations R336C and G307S, was B6 nonresponsive. This report of a ninth homocystinuric allele carrying two mutations in cis raises the possibility that double mutant alleles may be underestimated in homocystinuric patients. In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype-phenotype relationship. Hum Mutat 13:453-457, 1999. © 1999 Wiley-Liss, Inc.

IntroductionHomocystinuria due to cystathionine β-synthase (CBS) deficiency (MIM # 236200) is the most common inborn error of sulfur amino acid metabolism. It is inherited as an autosomal recessive trait. The frequency of the disease has been estimated between 1 in 200 000 and 1 in 335 000 (Mudd et al., 1989), though several lines of evidence indicate that this frequency might be higher (Mudd et al., 1995).Sulfur-containing amino acids, homocysteine, methionine and cysteine are linked by the remethylation cycle and the trans-sulfuration pathway (Fig. 26.1). CBS (shape l-serine hydrolyase; EC 4.2.1.22) catalyzes the condensation of homocysteine with serine to form the thioether cystathionine, a reaction requiring pyridoxal-phosphate as cofactor (Fig. 26.1, enzyme 2). Cystathionine is cleaved to cysteine and α-ketobutyrate by another pyridoxal-phosphate-dependent enzyme, γ-cystathionase (enzyme 3). The trans-sulfuration pathway ends converting sulfite to sulfate and is catalyzed by sulfite oxidase (enzyme 4), requiring a molybdenum cofactor. Conversion of methionine into homocysteine proceeds via methionine adenosyltransferase (enzyme 1) yielding S-adenosylmethionine, a methyl-group donor used in several transmethylation reactions, and S-adenosylhomocystein e, which is cleaved to adenosine and homocysteine. About 50% of homocysteine, not entering the trans-sulfuration pathway, is recycled into methionine. This step involves methyl transfer either from 5-methyl-tetrahydrofolate (THF), catalyzed by cobalamin-requiring 5-methyl THF-homocystei ne methyltransferase (methionine synthase, MS, enzyme 5), or from betaine, catalyzed by betaine-homocysteine methyltransferase (enzyme 6).