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Childhood apraxia of speech is a neurologic speech sound disorder in which children have difficulty constructing words and sounds due to poor motor planning and coordination of the articulators required for speech sound production. We report the case of a 3-year-old boy strongly suspected to have childhood apraxia of speech at 18 months of age who used multimodal communication to facilitate language development throughout his work with a speech language pathologist. In 18 months of an intensive structured program, he exhibited atypical rapid improvement, progressing from having no intelligible speech to achieving age-appropriate articulation. We suspect that early introduction of sign language by family proved to be a highly effective form of language development, that when coupled with intensive oro-motor and speech sound therapy, resulted in rapid resolution of symptoms., (Copyright © 2016 by the American Academy of Pediatrics.)

Purpose of Review: This article provides an analysis of the effectiveness of commonly used interventions for social pragmatic interventions for children with autism spectrum disorder (ASD) and social communication disorders., Recent Findings: Several evidence-based social skills interventions are emerging, including peer mentoring, social skills groups, and video modeling. Social stories are effective as supports for improved interactions but generalization is limited. Research supports the need for multimodality and individualized treatment programs. Research validates that video and visual learning is highly effective with children with ASD when utilized with specific, appropriate targets. Multiple studies have shown that picture-based communication systems are effective at improving functional communication with moderate effects on social communication. Despite limitations in research, there is strong evidence in the existing literature for the role of alternative augmentative communication in improving both functional and social communication., Summary: Social pragmatic interventions when individualized are effective for improving language, adaptive behavior and social skills.

Aim: To adopt an individualized approach to assess cytarabine (ara-C) hematotoxicity, we studied the relationship between pharmacogenetic variability in the cytidine deaminase gene (CDA) and ara-C toxicity in native peripheral blood mononuclear cells from 100 healthy volunteers., Materials & Methods: Peripheral blood mononuclear cells were incubated for 48 h with 3 µM ara-C, and cell viability was analyzed by flow cytometry with and without the addition of an equilibrative nucleoside transporter transport inhibitor. CDA promoter and exonic variants were genotyped to derive haplotypes for the CDA gene., Results: Significant between-subject variability was observed in ara-C toxicity (21-fold with 40.1% coefficient of variation compared with 1.2-fold within-subject variability [9.6% coefficient of variation]). Inhibition of hENT1 reversed ara-C cytotoxicity. The linked CDA promoter variants -451C>T, -92A>G, -31Del and the exonic 79A>C variant were associated with ara-C toxicity (p < 0.05). CDA*2A haplotype was associated with ara-C toxicity (p = 0.03)., Conclusion: Genetic polymorphisms within CDA may be risk factors for ara-C-induced hematotoxicity. Original submitted 6 October 2010; Revision submitted 29 November 2010.

Objective: Dendritic cells (DC) accumulate in atherosclerotic arteries where they can modulate atherogenesis. We investigated whether plasmin might alter the function of human DC., Methods and Results: Stimulation of monocyte-derived DC with plasmin elicited a time-dependent actin polymerization and chemotaxis comparable to that triggered by the standard chemoattractant formyl-methionyl-leucyl-phenylalanine. Plasmin triggered rapid activation of Akt and mitogen-activated protein kinases, followed by phosphorylation of the regulatory myosin light chain and chemotaxis. For the chemotactic DC migration, the activation of Akt and p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases were indispensable, as shown by pharmacological inhibitors. DC express Akt1 and Akt2, but not Akt3. However, in DC, plasmin activates exclusively Akt2 via a p38 mitogen-activated protein kinase-dependent pathway. Accordingly, knockdown of Akt2 with short-hairpin RNA, but not of Akt1, blocked the plasmin-induced extracellular signal-regulated kinase 1/2 activation and the chemotactic response. Moreover, plasmin-stimulated DC induced polarization of CD4(+) T cells toward the interferon-gamma-producing, proinflammatory Th1 phenotype. Consistent with a role for DC and adaptive immune response in atherogenesis, we demonstrate DC in human atherosclerotic vessels and show that plasmin is abundant in human atherosclerotic lesions, where it colocalizes with DC., Conclusions: Plasmin generation in the atherosclerotic vessel wall might contribute to accumulation of DC, activation of the adaptive immune response, and aggravation of atherosclerosis.

Activation of the serine/threonine kinase Akt is associated with aggressive clinical behavior of prostate cancer. We found that the human prostate cancer cell lines LNCaP and PC-3 express predominantly Akt1 and Akt2. Selective down-regulation of Akt1, but not Akt2, by short-hairpin RNA reduced the viability of prostate cancer cells. In addition, structurally different Akt inhibitors were cytotoxic for the prostate cancer cells, confirming that the Akt pathway is indispensable for their viability. We have purified the tetracyclic triterpenoids 3-oxo-tirucallic acid, 3-alpha-acetoxy-tirucallic acid, and 3-beta-acetoxy-tirucallic acid from the oleogum resin of Boswellia carterii to chemical homogeneity. The acetoxy-derivatives in particular potently inhibited the activities of human recombinant Akt1 and Akt2 and of constitutively active Akt immunoprecipitated from PC-3 cells, whereas inhibitor of nuclear factor-kappaB kinases remained unaffected. Docking data indicated that these tetracyclic triterpenoids form hydrogen bonds within the phosphatidylinositol binding pocket of the Akt pleckstrin homology domain. Accordingly, 3-beta-acetoxy-tirucallic acid did not inhibit the activity of Akt1 lacking the pleckstrin homology domain. In the prostate cancer cell lines investigated, these compounds inhibited the phosphorylation of cellular Akt and the Akt signaling pathways, including glycogen synthase kinase-3beta and BAD phosphorylation, nuclear accumulation of p65, the androgen receptor, beta-catenin, and c-Myc. These events culminated in the induction of apoptosis in prostate cancer, but not in nontumorigenic cells. The tirucallic acid derivatives inhibited proliferation and induced apoptosis in tumors xenografted onto chick chorioallantoic membranes and decreased the growth of pre-established prostate tumors in nude mice without overt systemic toxicity. Thus, tirucallic acid derivatives represent a new class of Akt inhibitors with antitumor properties.