Defective production of IL-18 and IL-12 by cord blood mononuclear cells influences the T helper-1 interferon gamma response to group B Streptococci

Human neonates are uniquely susceptible to group B streptococcal (GBS) infections. We have shown that neonatal mixed mononuclear cells have a deficiency in the production of the T helper-1 (Th-1) cytokine, interferon gamma (IFN-gamma), and that incubation of neonatal neutrophils with recombinant IFN-gamma corrects these neutrophil defects. IL-12 and the more recently described IL-18 are also Th-1 type cytokines that are able to induce the production of IFN-gamma in the presence of bacteria and bacterial products. We examine the ability of GBS to induce the production of IFN-gamma, IL-18, and IL-12 by cord blood mixed mononuclear cells and compared these results with the IFN-gamma, IL-18, and IL-12 response of mixed mononuclear cells from adult blood. We demonstrate that cord blood mixed mononuclear cells produced significantly less IFN-gamma, IL-18, and IL-12 in response to GBS compared with mixed mononuclear cells from adults. Cord blood mixed mononuclear cells' production of IFN-gamma is enhanced by added recombinant IL-18 and IL-12. The maximal cord blood cell production of IFN-gamma, in response to GBS, is achieved by priming the cells with both IL-18 and IL-12. We conclude that neonatal mixed mononuclear cells exhibit deficiencies in three main Th-1 type cytokine responses, IFN-gamma, IL-12, and IL-18. This combined Th-1 type cytokine deficiency may contribute to the enhanced susceptibility of the human neonate to GBS and other microbial infections.     

Barbie or Betty? Preschool children's preference for branded products and evidence for gender-linked differences

Children in the United Kingdom watch more television and are exposed to more advertising than children in any other European country. This article investigates the extent to which preschool children (aged 4-5 years) prefer brands advertised on television. Seventy-five children were interviewed and given a choice task in which they had to select the product, from eight pairs each comprising a branded and nonbranded product, that children of their own age and gender preferred. Products included popular drinks, snacks, toys, breakfast cereals, and sportswear. Nonbranded control products were carefully selected as close perceptual matches for the branded advertised products. Yet, on 68% of occasions, children chose the branded, advertised product in preference to the nonbranded product. This preference was reliably higher for girls (78%) than boys (58%). Gender-linked differences are discussed in relation to socialization theory and to girls' greater verbal ability and emotional sensitivity.     

The use of magnification in a preventive approach to caries detection.

OBJECTIVE: The aim of this study was to demonstrate the effect of low-powered magnification on the accuracy of caries detection and to compare it to the accuracy of unaided vision. METHOD AND MATERIALS: Five dental models were prepared with extracted, unrestored, human permanent premolars, molars, and canines. Dental examinations were undertaken in simulated clinical conditions by seven dentists using both unaided and magnified vision. A true diagnosis was obtained by histologic sectioning, thereby allowing diagnostic accuracy to be calculated. RESULTS: The sensitivity of diagnosis, representing the percentage of diseased sites found correctly, was significantly greater when magnification was used. There was no statistically significant difference in the specificities, or percentages of correctly identified healthy sites, between magnification and unaided vision. CONCLUSION: Magnification, although not perfect, improved significantly on the accuracy of diagnosis and can therefore be recommended for caries detection.     

Searching for moderators and mediators of pharmacological treatment effects in children and adolescents with anxiety disorders

OBJECTIVE: To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders. METHOD: The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome. RESULTS: No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p < .001). Patients with social phobia (p < .05) and greater severity of illness (p < .001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p < .001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement. CONCLUSIONS: In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.     

Therapeutics of aggression in children

This paper examines the phenomenology, aetiology and therapeutics of childhood aggression that arises as part of a disruptive behaviour disorder. Phenomenology is discussed with an emphasis on treatment implications. Reviewed studies show that aggressive behaviour exhibits both episodicity and considerable individual stability. Aetiological theories are reviewed with emphasis on the interplay between biological and socio-environmental factors. Both factors are centrally involved in the development and treatment of aggression. A review of double-blind, placebo-controlled medication studies is presented. A computer-based, literature search using Medline and PsychInfo was conducted to locate all potentially relevant articles published in the past 20 years. It was found that there are various treatments available for reducing paediatric aggression including psychotherapeutic and psychopharmacological treatments. There are data to support the use of psychostimulants, lithium and antipsychotics, while data for other agents are only beginning to accumulate. Various pharmacological treatments can reduce aggression in children. However, given the role of both biological and social factors in the development of aggression, multimodal treatment may ultimately provide maximal benefits.     

Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer

BackgroundSTK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.MethodsForty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.ResultsIn the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype.ConclusionsOur retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.