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Although the American Academy of Pediatrics has long recommended universal autism-specific screening at well-child pediatric visits, implementation challenges in primary care settings interfere with high-fidelity universal autism screening. These challenges delay autism identification for some children, leading to delays in needed services and supports. Prior findings indicate that new solutions must be developed to bridge the gap in access to autism screening for families, particularly among those who are under-resourced. One approach is expanding screening to other community settings, such as childcare centers, but there are barriers to this approach, which this commentary aims to address. We discuss challenges and barriers in childcare screening identified through our recently completed pilot study screening for autism in childcare centers, with suggested strategies to address them. These challenges include hesitation among childcare staff to guide conversations or concerns about autism, and stigma around autism diagnosis and presentation. Other challenges relate to emerging concerns regarding legal, ethical, and professional roles and responsibilities surrounding informed consent and data privacy, as well as the identification of children without timely follow-up evaluation and services. There is a need for increasing public awareness as an essential component of autism screening across settings. Our commentary discusses different considerations and practice strategies to meet these needs.

Autism-specific screening and developmental surveillance in primary care aid identification of autism. In this study, we assessed primary care clinicians’ (PCCs’) reported confidence in screening scores from the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and in their own diagnostic impressions. Four PCCs provided data for 50 children aged 16–36 months for whom they had any developmental concern. PCCs’ diagnostic impressions were “Definitely Autism” for 15 children (30%), “Unsure—Needs Further Evaluation” for 25 children (50%) and “Definitely Not Autism” for 10 children (20%). They reported High Confidence on the screener score in 33 cases (66%). Of the 17 cases for whom PCCs reported having Low Confidence on the M-CHAT-R, 14 children (82.3%) had a Low Likelihood score, with no significant association between M-CHAT-R likelihood and PCC’s confidence in the screening score. PCCs’ diagnostic impressions were concordant with the M-CHAT-R autism likelihood in 42% of cases, with a significantly higher mean in confidence rating when compared to the non-concordant cases. Language development and social engagement were the most frequently endorsed concerns by PCCs, with significant associations between these concerns and M-CHAT-R likelihood. Our results suggest that, when developmental concerns exist, PCCs may place greater confidence in the M-CHAT-R when scores indicate a higher likelihood of autism, and that confidence in their own diagnostic impressions may be associated with concordance with the screener score.

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which—in vitro—resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies.

The insulin-like growth factor-1 receptor (IGF-IR) and the human polyomavirus JCV protein, T-antigen cooperate in the transformation of neuronal precursors in the cerebellum, which may be a contributing factor in the development of brain tumors. Because it is not clear why T-antigen requires IGF-IR for transformation, we investigated this process in neural progenitors from IGF-IR knockout embryos (ko-IGF-IR) and from their wild-type nontransgenic littermates (wt-IGF-IR). In contrast to wt-IGF-IR, the brain and dorsal root ganglia of ko-IGF-IR embryos showed low levels of the antiapoptotic protein Survivin, accompanied by elevated numbers of apoptotic neurons and an earlier differentiation phenotype. In wt-IGF-IR neural progenitors in vitro , induction of T-antigen expression tripled the expression of Survivin and accelerated cell proliferation. In ko-IGF-IR progenitors induction of T-antigen failed to increase Survivin, resulting in massive apoptosis. Importantly, ectopic expression of Survivin protected ko-IGF-IR progenitor cells from apoptosis and siRNA inhibition of Survivin activated apoptosis in wt-IGF-IR progenitors expressing T-antigen. Our results indicate that reactivation of the antiapoptotic Survivin may be a critical step in JCV T-antigen-induced transformation, which in neural progenitors requires IGF-IR.

Presentamos un estudio multicéntrico realizado a través de una encuesta en línea a 1826 familias de personas con TEA de Argentina, Brasil, Chile, México, Perú, República Dominicana, Uruguay y Venezuela. Nuestro objetivo es describir el impacto de la pandemia –y el aislamiento social– en la conducta, el estado de ánimo, el sueño y la alimentación de las personas con TEA. A tal fin hemos relevado características sociodemográficas, habitacionales y modalidad de confinamiento. Analizamos los efectos de la discontinuidad de los servicios educativos y terapéuticos y valoramos los alcances de las intervenciones a distancia. Algunas de las consecuencias del confinamiento –obligatorio para la mayoría– han sido el aumento de irritabilidad en las personas con TEA, el incremento de la conducta de deambular, mayores niveles de ansiedad, dificultades en alimentación, sueño y concentración. La mayor parte de las familias han notado retrocesos en sus hijos durante el encierro. Se destacan los efectos beneficiosos de salidas y paseos. Muchos tratamientos y clases se han suspendido. Se subrayan positivamente las intervenciones a distancia. La crisis actual debería ser una oportunidad para reorganizar dispositivos de educación y tratamiento, atendiendo a la necesidad de cambios, con una perspectiva más ecológica, inclusiva y amigable con el autismo.

The aim of this study was to determine whether transforming growth factor-β 1 (TGF-β 1 ) induces the synthesis, release and gene expression of urokinase-type plasminogen activator (uPA) in hepatic stellate cells. In addition to stimulating collagen production, TGF-β 1 induced the morphological and phenotypical changes characteristic of hepatic stellate cell activation. However, these changes accentuated in cells previously activated with acetaldehyde. TGF-β 1 increased to 2-fold uPA activity in lysates from quiescent cells, and to 3.5-fold in activated cells, and induced uPA gene expression to the same extent in both activated and non-activated cells. TGF-β 1 had a modest stimulatory action on the release of uPA into the conditioned medium, but reduced acetaldehyde-induced release, as demonstrated by Western blot analysis. In accord, whereas TGF-β 1 produces no effect on uPA activity in the conditioned media from quiescent cells, it significantly reduces the stimulatory action of acetaldehyde. These results show that the activity and gene expression of uPA are regulated by both acetaldehyde and TGF-β 1 and that the proteolytic activity in the extracellular space is reduced by the influence of TGF-β 1 . Further studies on the molecular mechanisms responsible for the regulation of the plasminogen system by TGF-β 1 and other molecules in the presence of acetaldehyde will contribute to a better understanding of the processes involved in fibrogenesis.

The aim of this study was to determine whether transforming growth factor-beta1 (TGF-beta1) induces the synthesis, release and gene expression of urokinase-type plasminogen activator (uPA) in hepatic stellate cells. In addition to stimulating collagen production, TGF-beta1 induced the morphological and phenotypical changes characteristic of hepatic stellate cell activation. However, these changes accentuated in cells previously activated with acetaldehyde. TGF-beta1 increased to 2-fold uPA activity in lysates from quiescent cells, and to 3.5-fold in activated cells, and induced uPA gene expression to the same extent in both activated and non-activated cells. TGF-beta1 had a modest stimulatory action on the release of uPA into the conditioned medium, but reduced acetaldehyde-induced release, as demonstrated by Western blot analysis. In accord, whereas TGF-beta1 produces no effect on uPA activity in the conditioned media from quiescent cells, it significantly reduces the stimulatory action of acetaldehyde. These results show that the activity and gene expression of uPA are regulated by both acetaldehyde and TGF-beta1 and that the proteolytic activity in the extracellular space is reduced by the influence of TGF-beta1. Further studies on the molecular mechanisms responsible for the regulation of the plasminogen system by TGF-beta1 and other molecules in the presence of acetaldehyde will contribute to a better understanding of the processes involved in fibrogenesis.

The aim of this study was to determine whether transforming growth factor-β1 (TGF-β1) induces the synthesis, release and gene expression of urokinase-type plasminogen activator (uPA) in hepatic stellate cells. In addition to stimulating collagen production, TGF-β1 induced the morphological and phenotypical changes characteristic of hepatic stellate cell activation. However, these changes accentuated in cells previously activated with acetaldehyde. TGF-β1 increased to 2-fold uPA activity in lysates from quiescent cells, and to 3.5-fold in activated cells, and induced uPA gene expression to the same extent in both activated and non-activated cells. TGF-β1 had a modest stimulatory action on the release of uPA into the conditioned medium, but reduced acetaldehyde-induced release, as demonstrated by Western blot analysis. In accord, whereas TGF-β1 produces no effect on uPA activity in the conditioned media from quiescent cells, it significantly reduces the stimulatory action of acetaldehyde. These results show that the activity and gene expression of uPA are regulated by both acetaldehyde and TGF-β1 and that the proteolytic activity in the extracellular space is reduced by the influence of TGF-β1. Further studies on the molecular mechanisms responsible for the regulation of the plasminogen system by TGF-β1 and other molecules in the presence of acetaldehyde will contribute to a better understanding of the processes involved in fibrogenesis. Copyright © 2005 S. Karger AG, Basel [PUBLICATION ABSTRACT]