Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio‐facio‐cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r‐FLACC, Wang‐Baker scale, NPSI, BPI, NCCPC‐R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs‐QL, SF‐36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle‐skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.     

The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites

Summary: Exposure to irradiated Plasmodium sporozoites (g‐spz) results in protection against malaria. Like infectious spz, g‐spz colonize hepatocytes to undergo maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (IHMC). We demonstrated that P. berghei g‐spz‐immune murine IHMC adoptively transfer protection to naive recipients. Characterization of intrahepatic CD4+ T cells revealed an immediate, albeit transient, response to g‐spz, while the response of CD8+ T cells is delayed until acquisition of protection. It is presumed that activated CD8+ T cells home to the liver to die; g‐spz‐induced CD8+CD45RBloCD44hi T cells, however, persist in the liver, but not the spleen, during protracted protection. The association between CD8+CD45RBloCD44hi T cells and protection has been verified using MHC class I and CD1 knockout mice and mice with disrupted liver stage parasites. Based on kinetic studies, we propose that interferon‐g, presumably released by intrahepatic effector CD8+ T cells, mediates protection; the persistence of CD8+ T cells is, in turn, linked to Plasmodium antigen depots and cytokines released by CD4+ T cells and/or NK T cells.     

Mutations in VMK1, a mitogen-activated protein kinase gene, affect microsclerotia formation and pathogenicity in Verticillium dahliae

Verticillium dahliae is an important soil-borne fungal pathogen that causes vascular wilt diseases in a large variety of important crop plants. Due to its persistence in the soil, control of Verticillium wilt relies heavily on soil fumigation. The global ban on methyl bromide, a highly effective soil fumigant, poses an urgent need to develop alternative control measures against Verticillium wilt; and these might be more forthcoming with a better understanding of the molecular and cellular mechanisms that underpin the pathogenicity of V. dahliae. In this study, we assessed the role in growth, development, and pathogenicity of VMK1, a gene encoding a mitogen-activated protein (MAP) kinase (hence, Verticillium MAP Kinase 1). Disruption of VMK1 via Agrobacterium tumefaciens-mediated transformation, in two V. dahliae isolates, one from lettuce and the other from tomato, resulted in severely reduced virulence in diverse host plants, suggesting that VMK1 is essential for pathogenicity and that the MAP kinase-mediated signaling pathway has a conserved role in fungal pathogenicity. The vmk1 mutants also exhibited reduced conidiation and microsclerotia formation, suggesting that the gene is important for multiple cellular processes. P.R. and R.G.B. equally contributed to the work     

Effect of oestradiol on mouse uterine epithelial cell tumour necrosis factor-alpha release is mediated through uterine stromal cells

Oestradiol-17beta (Oe(2)) stimulates uterine epithelial cell proliferation and is critical for normal uterine differentiation and secretory function. Oe(2) can act directly on the epithelium via the epithelial oestrogen receptor (OR) or indirectly via the OR-positive underlying stroma. A primary role for epithelial-stromal interactions has been established for mediating steroid hormone action in the uterus. This study was undertaken to determine the mode of Oe(2) action in regulating epithelial cell cytokine release in the uterus. Mouse uterine epithelial and stromal cells were isolated and cultured separately. Transepithelial resistance (TER) was monitored with an EVOM voltohmmeter to determine monolayer polarity and integrity. Epithelial cells grown alone or in coculture with stromal cells were treated with Oe(2). Supernatants collected were assayed for transforming growth factor-beta (TGF-beta) and tumour necrosis factor-alpha (TNF-alpha) by bioassay and enzyme-linked immunosorbent assay, respectively. While Oe(2) treatment of epithelial cells led to a significant decrease in TER, the amount of TNF-alpha released was not altered. However, when epithelial cells were cocultured with stromal cells and treated with Oe(2), apical TNF-alpha release was significantly decreased, compared to cells not treated with hormone. As determined by oestrogen receptor antagonist studies, Oe(2) primed epithelial cells for the action of the stromal paracrine factor(s). In contrast, TGF-beta release by epithelial cells was not affected by Oe(2) when grown alone or in the presence of stromal cells. These studies indicate that Oe(2) has both direct and indirect effects on the uterine epithelium. While epithelial monolayer integrity is directly influenced by Oe(2), TNF-alpha release in response to Oe(2) is dependent on the presence of stromal cells, indicating that paracrine communication is necessary for steroid regulation of some but not all cytokines.     

Biological Activity of a Mouse-Human Chimeric Immunoglobulin G2 Antibody to Cryptococcus neoformans Polysaccharide

The variable regions of the heavy and light chains of the protective murine monoclonal antibody (MAb) 2H1 (m2H1) were expressed with the human constant region genes for immunoglobulin G2 (IgG2) and kappa, respectively, to construct a chimeric antibody (ch2H1). ch2H1 retains the specificity of the parent MAb, exhibits biological activity, and lacks the toxicity of the parent murine IgG1 in chronically infected mice.     

Enamel structure and composition in the tricho-dento-osseous syndrome

Tricho-dento-osseous syndrome (TDO) is an autosomal dominant disorder characterized by curly hair, hypoplastic enamel, taurodontism, and dense bone. The purpose of this investigation was to characterize the enamel defects in a TDO population in North Carolina. Twelve TDO teeth and 12 normal teeth were examined. The enamel thickness was decreased in all TDO teeth ranging from having no enamel to about 60% the thickness of normal teeth. Half of the TDO teeth had primarily prismless enamel while the remainder had at least occasional areas of prismatic enamel. TDO enamel crystallites appeared similar to normal crystallites with TEM. The mineral per volume of TDO enamel (n = 9) (68.5%) was significantly less, on average, compared with normal enamel (n = 8) (84.5). The genetic mutation responsible for the TDO phenotype results in alteration of a developmental pathway(s) common to hair, teeth and bone. This further illustrates that these embryologically diverse tissues share common developmental controls at the molecular level.     

Topical treatments for seasonal allergic conjunctivitis: systematic review and meta-analysis of efficacy and effectiveness

BACKGROUND: Evidence for the effectiveness of topical treatments, in providing symptomatic relief from ocular allergy, remains uncertain. AIMS: To assess the effectiveness and relative efficacy of topical treatments for the management of seasonal allergic conjunctivitis. DESIGN OF STUDY: A systematic review and meta-analysis. SETTING: A literature search of the Cochrane Library, Medline, and EMBASE bibliographic databases. METHOD: Double-masked randomised controlled trials were identified, that compared the use of topical mast cell stabilisers (sodium cromoglycate, nedocromil, lodoxamide) with placebo, topical antihistamines with placebo, and topical mast cell stabilisers with topical antihistamines. RESULTS: A meta-analysis of six trials showed that patients using sodium cromoglycate were 17 times (95% confidence interval [CI] = 4 to 78) more likely to perceive benefit compared with those using a placebo, although this estimate may be partially influenced by publication bias. Five trials indicated that those patients using nedocromil were 1.8 times (95% CI = 1.3 to 2.6) more likely to perceive their allergy to be moderately or totally controlled than those using a placebo. Four trials showed that those using antihistamines were 1.3 times (95% CI = 0.8 to 2.2) more likely to perceive a 'good' treatment effect than those using mast cell stabilisers, although this beneficial effect was not statistically significant. Limited evidence suggests that antihistamines might have a faster therapeutic effect compared to mast cell stabilisers. CONCLUSION: Overall, these findings confirm the benefit of topical mast cell stabilisers and antihistamines over placebo for the treatment of allergic conjunctivitis. There is, however, insufficient evidence to recommend the use of one type of medication over another. Treatment preferences should therefore be based on convenience of use (with reduced frequency of instillation for some preparations), patient preference, and costs, especially as important side effects were not reported with any medication.     

Clonal Diversity and Turnover of Streptococcus mitis bv. 1 on Shedding and Nonshedding Oral Surfaces of Human Infants during the First Year of Life

Streptococcus mitis bv. 1 is a pioneer colonizer of the human oral cavity. Studies of its population dynamics within parents and their infants and within neonates have shown extensive diversity within and between subjects. We examined the genetic diversity and clonal turnover of S. mitis bv. 1 isolated from the cheeks, tongue, and primary incisors of four infants from birth to 1 year of age. In addition, we compared the clonotypes of S. mitis bv. 1 isolated from their mothers' saliva collected in parallel to determine whether the mother was the origin of the clones colonizing her infant. Of 859 isolates obtained from the infants, 568 were unique clones. Each of the surfaces examined, whether shedding or nonshedding, displayed the same degree of diversity. Among the four infants it was rare to detect the same clone colonizing more than one surface at a given visit. There was little evidence for persistence of clones, but when clones were isolated on multiple visits they were not always found on the same surface. A similar degree of clonal diversity of S. mitis bv. 1 was observed in the mothers' saliva as in their infants' mouths. Clones common to both infant and mothers' saliva were found infrequently suggesting that this is not the origin of the infants' clones. It is unclear whether mucosal immunity exerts the environmental pressure driving the genetic diversity and clonal turnover of S. mitis bv. 1, which may be mechanisms employed by this bacterium to evade immune elimination.