Objective To investigate the effect of dietary supplementation with a probiotic on feeding tolerance and gastrointestinal motility in healthy formula-fed preterm infants. Study design Thirty preterm ...newborns were enrolled; 10 were exclusively breast-fed, and the remaining 20 were randomly assigned in a double-blind manner to receive either Lactobacillus reuteri ATCC 55730 (at dose of 1 × 108 colony forming units a day) or placebo for 30 days. Clinical symptoms of gastrointestinal function (regurgitation, vomiting, inconsolable crying, and evacuation) and physiological variables (gastric electrical activity and emptying) were recorded before and after the dietary intervention. Results Body weight gains per day were similar for the 3 groups, and no adverse events were recorded. Newborns receiving probiotics showed a significant decrease in regurgitation and mean daily crying time and a larger number of stools compared with those given placebo. Gastric emptying rate was significantly increased, and fasting antral area was significantly reduced in both the newborns receiving L. reuteri and breast-fed newborns compared with placebo. Conclusions Our results suggest a useful role for L. reuteri supplementation in improving feeding tolerance and gut function in formula-fed preterm newborns.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Preconceptional maternal immunity against CMV is not protective in terms of fetal damage.•Neurodevelopmental and hearing sequelae are not affected by the type of maternal CMV infection.•Congenital ...CMV may be a relevant problem even in case of pre-pregnancy immunization.
Natural history and long term prognosis of congenital cytomegalovirus (CMV) disease according to maternal primary versus non-primary infection are not clearly documented.
To investigate clinical, laboratory and neuroimaging features at onset and long term outcome of congenitally CMV-infected patients born to mothers with non-primary infection compared with a group of patients born to mothers with primary infection.
Consecutive neonates born from 2002 to 2015 were considered eligible for the study. Patients underwent clinical, laboratory and instrumental investigation, and audiologic and neurodevelopmental evaluation at diagnosis and during the follow up.
A cohort of 158 congenitally infected children was analyzed. Ninety-three were born to mothers with primary CMV infection (Group 1) and 65 to mothers with a non-primary infection (Group 2). Eighty-eight infants had a symptomatic congenital CMV disease: 49 (46.2%) in Group 1 and 39 (60%) in Group 2. Maternal and demographic characteristics of patients of Group 1 and Group 2 were comparable, with the exception of prematurity and a 1-min Apgar score less than 7, which were more frequent in Group 2 compared to Group 1. Prevalence of neuroimaging findings did not significantly differ between the two groups. An impaired neurodevelopmental outcome was observed in 23.7% of patients of Group 1 and in 24.6% cases of Group 2. Similarly, the frequency of hearing loss did not differ between the two groups (25.8% versus 26.2%, respectively).
Neurodevelopmental and hearing sequelae are not affected by the type of maternal CMV infection. Preventing strategies should be developed for both primary and non-primary infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Congenital cytomegalovirus (cCMV) infection is a frequent cause of neurosensory impairment. Ocular abnormalities and visual impairment have been reported in a high percentage of ...symptomatic infants, whereas they are considered uncommon in asymptomatic ones. The paucity of data has made difficult to reach clear recommendations on the ophthalmological follow-up that should be provided.
Methods
250 patients with cCMV infection (123 symptomatic) were enrolled and underwent a series of age-appropriate ophthalmologic, audiologic, and neurodevelopmental examinations from 2002 to 2022.
Results
Funduscopic abnormalities were identified at onset in 16/123 (13%) symptomatic infants and in none of the asymptomatic ones (
p
< 0.001). Chorioretinitis lesions were the most common findings (10/16 cases), while the others showed retinal scars. Lesions were bilateral in 4 patients. No later onset retinal lesions were detected, nor in symptomatic or in asymptomatic children. Five of the 16 (31.5%) symptomatic and none of the asymptomatic subjects showed visual impairment al the last evaluation (
p
< 0.001). All patients with unfavorable outcome had also neurological impairment. Among symptomatic patients, ocular lesions were associated with central nervous system (CNS) pathological findings in prenatal ultrasonography (
p
0.05) and with clinical signs of CNS involvement at birth (
p
0.046). No correlation was found with the type of maternal infection and pathological neuroimaging.
Conclusions
Chorioretinal lesions are a fairly common finding at birth in neonates with symptomatic cCMV, often associated with long term visual impairment. Asymptomatic infants do not show ophthalmological abnormalities in the short or long term. This information is relevant both to parental counseling and to cost-effective patient management.
Congenital syphilis presents a significant global burden, contributing to fetal loss, stillbirth, neonatal mortality, and congenital infection. Despite the target established in 2007 by the World ...Health Organization (WHO) of fewer than 50 cases per 100,000 live births, the global incidence is on the rise, particularly in low- and middle-income regions. Recent data indicate a rate of 473 cases per 100,000 live births, resulting in 661,000 total cases of congenital syphilis, including 355,000 adverse birth outcomes such as early fetal deaths, stillbirths, neonatal deaths, preterm or low-birth-weight births, and infants with clinical congenital syphilis. Alarmingly, only 6% of these adverse outcomes occurred in mothers who were enrolled, screened, and treated. Unlike many neonatal infections, congenital syphilis is preventable through effective antenatal screening and treatment of infected pregnant women. However, despite available screening tools, affordable treatment options, and the integration of prevention programs into antenatal care in various countries, congenital syphilis remains a pressing public health concern worldwide. This review aims to summarize the current epidemiology, transmission, and treatment of syphilis in pregnancy, as well as to explore global efforts to reduce vertical transmission and address the reasons for falling short of the WHO elimination target.
Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many ...pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly G
) coupled receptors, are mutually exclusive with Gα
oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the G
pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would ...require network-centered approaches combined with atomistic simulations. The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect. Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Ras superfamily comprises many guanine nucleotide-binding proteins (G proteins) that are essential to intracellular signal transduction. The guanine nucleotide-dependent intrinsic flexibility ...patterns of five G proteins were investigated in atomic detail through Molecular Dynamics simulations of the GDP- and GTP-bound states (S(GDP) and S(GTP), respectively). For all the considered systems, the intrinsic flexibility of S(GDP) was higher than that of S(GTP), suggesting that Guanine Exchange Factor (GEF) recognition and nucleotide switch require higher amplitude motions than effector recognition or GTP hydrolysis. Functional mode, dynamic domain, and interaction energy correlation analyses highlighted significant differences in the dynamics of small G proteins and Gα proteins, especially in the inactive state. Indeed, S(GDP) of Gα(t), is characterized by a more extensive energy coupling between nucleotide binding site and distal regions involved in GEF recognition compared to small G proteins, which attenuates in the active state. Moreover, mechanically distinct domains implicated in nucleotide switch could be detected in the presence of GDP but not in the presence of GTP. Finally, in small G proteins, functional modes are more detectable in the inactive state than in the active one and involve changes in solvent exposure of two highly conserved amino acids in switches I and II involved in GEF recognition. The average solvent exposure of these amino acids correlates in turn with the rate of GDP release, suggesting for them either direct or indirect roles in the process of nucleotide switch. Collectively, nucleotide binding changes the information flow through the conserved Ras-like domain, where GDP enhances the flexibility of mechanically distinct portions involved in nucleotide switch, and favors long distance allosteric communication (in Gα proteins), compared to GTP.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increasingly available genomic sequencing data are exploited to identify genes and variants contributing to diseases, particularly cancer. Traditionally, methods to find such variants have relied ...heavily on allele frequency and/or familial history, often neglecting to consider any mechanistic understanding of their functional consequences. Thus, while the set of known cancer‐related genes has increased, for many, their mechanistic role in the disease is not completely understood. This issue highlights a wide gap between the disciplines of genetics, which largely aims to correlate genetic events with phenotype, and molecular biology, which ultimately aims at a mechanistic understanding of biological processes. Fortunately, new methods and several systematic studies have proved illuminating for many disease genes and variants by integrating sequencing with mechanistic data, including biomolecular structures and interactions. These have provided new interpretations for known mutations and suggested new disease‐relevant variants and genes. Here, we review these approaches and discuss particular examples where these have had a profound impact on the understanding of human cancers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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