Natural cytotoxicity in the neonate: high levels of lymphokine activated killer (LAK) activity.

In 28 healthy full-term newborns the percentage of circulating cells expressing the Leu7 antigen, the marker of natural killer (NK) cells, was significantly lower than in healthy adults. However, newborns and adults did not differ with regard to the percentage of cells reacting with the Leulla, Leullc and TEC NK-1, monoclonal antibodies directed against the IgG Fc receptor of killer cells. Spontaneous NK activity of neonatal cells was profoundly reduced compared to the adult. In contrast, antibody dependent cellular cytotoxicity and NK-like activity generated in mixed lymphocyte cultures were similar in the two groups and lymphokine-activated killer cell (LAK) activity was high in the neonate. Natural killing is thought to play an important role in antiviral immunity since the neonate has a deficient capacity to deal with viral infections. Consequently, the present data indicate either that spontaneous NK is the most informative in vitro measure of newborn natural cytotoxicity in vivo, or, alternatively, that natural killing is not as important in antiviral immunity as previously suggeste

Sustained Exposure to the Widely Used Herbicide Atrazine: Altered Function and Loss of Neurons in Brain Monoamine Systems

The widespread use of atrazine (ATR) and its persistence in the environment have resulted in documented human exposure. Alterations in hypothalamic catecholamines have been suggested as the mechanistic basis of the toxicity of ATR to hormonal systems in females and the reproductive tract in males. Because multiple catecholamine systems are present in the brain, however, ATR could have far broader effects than are currently understood. Catecholaminergic systems such as the two major long-length dopaminergic tracts of the central nervous system play key roles in mediating a wide array of critical behavioral functions. In this study we examined the hypothesis that ATR would adversely affect these brain dopaminergic systems. Male rats chronically exposed to 5 or 10 mg/kg ATR in the diet for 6 months exhibited persistent hyperactivity and altered behavioral responsivity to amphetamine. Moreover, when measured 2 weeks after the end of exposure, the levels of various monoamines and the numbers of tyrosine hydroxylase-positive (TH(+)) and -negative (TH(−)) cells measured using unbiased stereology were reduced in both dopaminergic tracts. Acute exposures to 100 or 200 mg/kg ATR given intraperitoneally to evaluate potential mechanisms reduced both basal and potassium-evoked striatal dopamine release. Collectively, these studies demonstrate that ATR can produce neurotoxicity in dopaminergic systems that are critical to the mediation of movement as well as cognition and executive function. Therefore, ATR may be an environmental risk factor contributing to dopaminergic system disorders, underscoring the need for further investigation of its mechanism(s) of action and corresponding assessment of its associated human health risks

Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2)

AbstractThe activation-induced cytidine deaminase (AID) gene, specifically expressed in germinal center B cells in mice, is a member of the cytidine deaminase family. We herein report mutations in the human counterpart of AID in patients with the autosomal recessive form of hyper-IgM syndrome (HIGM2). Three major abnormalities characterize AID deficiency: (1) the absence of immunoglobulin class switch recombination, (2) the lack of immunoglobulin somatic hypermutations, and (3) lymph node hyperplasia caused by the presence of giant germinal centers. The phenotype observed in HIGM2 patients (and in AID−/− mice) demonstrates the absolute requirement for AID in several crucial steps of B cell terminal differentiation necessary for efficient antibody responses

Use of the internet by Italian pediatricians: habits, impact on clinical practice and expectations

<p>Abstract</p> <p>Background</p> <p>Medical professionals go online for literature searches and communication with families.</p> <p>We administered a questionnaire to members of the Italian Society of Pediatrics to assess determinants of their use of the Internet, of social platforms and of personal health records during clinical practice.</p> <p>Methods</p> <p>All the 9180 members of the Italian Society of Pediatrics were invited to fill in a questionnaire concerning use of the Internet and usefulness of Internet-based tools during clinical practice. The questionnaire was administered through the SurveyMonkey^®web platform. Logistic regression analysis was used to study factors affecting use and influence of the Internet in clinical practice.</p> <p>Results</p> <p>A total of 1335 (14.5%) members returned the questionnaire. Mean age was 49.2 years, 58.6% were female. 32.3% had access to the Internet through a Smartphone. 71.9% of respondents used the Internet during clinical practice, mainly searching for guidelines and drug references. Use of the Internet during clinical practice was more frequent among younger pediatricians (OR 0.964; 95% CI 0.591-0.978), males (OR 1.602; 95% CI 1.209-2.123) and those living in Northern and Central Italy (OR 1.441; 95% CI 1.111-1.869), while it was lower among family pediatricians. 94.6% of respondents were influenced in their clinical practice by information found on the Internet, in particular younger pediatricians (OR 0.96, 95% CI 0.932-0.989), hospital pediatricians (OR 2.929, 95% CI 1.708-5.024), and other pediatric profiles (OR 6.143, 95%CI 1.848-20.423). 15.9% of respondents stated that social networks may be useful in pediatric practice. Slightly more than half (50.5%) of respondents stated that personal health records may be clinically relevant. Registrars and hospital pediatricians were more likely to perceive personal health records as useful tools for clinical practice. Additional resources pediatricians would like to access were free bibliographic databases and tools for interacting with families.</p> <p>Conclusions</p> <p>Italian pediatricians frequently use the Internet during their practice. One-third of them access the Internet through a Smartphone. Interaction with families and their empowerment can be improved by the use of Internet tools, including personal health records, toward which respondents show a significant interest. Though, they show a general resistance to the introduction of social networks in clinical practice.</p

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999&#8211;2019)

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20\ua0years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy

Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome

Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS

Inflammatory and Immunological parameters in adults with Down syndrome

<p>Abstract</p> <p>Background</p> <p>The increase in life expectancy within the general population has resulted in an increasing number of elderly adults, including patients with Down syndrome (DS), with a current life expectancy of about 50 years. We evaluate the parameters of humoral and cellular immune response, the quantitative expression of the regulator of calcineurin1 gene (RCAN1) and the production of cytokines. The study group consisted of adults DS (n = 24) and a control group with intellectual disability without Down syndrome (ID) (n = 21) and living in a similar environmental background. It was evaluated serology, immunophenotyping, the quantitative gene expression of RCAN1 and the production of cytokines.</p> <p>Results</p> <p>In the DS group, the results showed an increase in NK cells, CD8, decreased CD19 (p < 0.05) and an increase spontaneous production of IFNgamma, TNFalpha and IL-10 (p < 0.05). There was not any difference in RCAN1 gene expression between the groups.</p> <p>Conclusions</p> <p>These data suggest a similar humoral response in the two groups. The immunophenotyping suggests sign of premature aging of the immune system and the cytokine production show a proinflammatory profile.</p

Impairment of circulating endothelial progenitors in Down syndrome

<p>Abstract</p> <p>Background</p> <p>Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome.</p> <p>Methods</p> <p>Circulating endothelial progenitors of Down syndrome affected individuals were isolated, <it>in vitro </it>cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of <it>CXCL12 </it>gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis.</p> <p>Results</p> <p>We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells.</p> <p>Conclusions</p> <p>Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.</p