Knowledge, attitude, and practices of parents regarding the red flags of developmental milestones in children aged 0-5 years in Karachi, Pakistan: a cross-sectional study.

BACKGROUND: Developmental delays in children are assessed in four basic domains: gross motor, fine motor, social, and language. Early years of life are crucial in a child's development, so it is imperative that parents be aware of developmental milestones to facilitate early diagnosis and treatment in case of a developmental delay. This study assessed parental knowledge, attitude, and practices regarding children's developmental milestones and associated "red flags". METHODS: A cross-sectional study was conducted at the Department of Pediatrics at Liaquat National Hospital, Karachi. 390 parents, who had at least one child under 5 years of age, with no diagnosed developmental delay, were interviewed during outpatient clinic visits. The questionnaire consisted of three components to assess parental knowledge, attitude, and practices. RESULTS: 59% and 54% of parents had poor knowledge of gross and fine motor milestones respectively; In the social domain, 56% of the respondents had inadequate knowledge. 42% had inadequate knowledge of language milestones; 29% of parents strongly agreed that their pediatricians provide satisfactory information regarding red flags of developmental milestones. 60% of parents strongly agreed that their child's developmental delay would be a cause of concern for them. In the case of developmental delay, 55% of parents said they would consult a general pediatrician, 11% preferred a pediatric neurologist, 21% opted for a developmental pediatrician and 13% opted for a family physician. Residence and family systems were found to be associated with language-related milestones with significantly higher odds of knowledge among urban residents than rural ones and a significantly lower likelihood of language milestones knowledge among joint families than nuclear families. Female gender was found to be significantly associated with positive attitude. CONCLUSION: The majority of our respondents showed considerably poor knowledge regarding developmental milestones. This highlights the need to devise ways to educate parents on this subject to enable them to vigilantly monitor their child's developmental status and any associated abnormalities and ultimately facilitate the right course of action.

Inhibition of thrombospondin-1 reduces glutathione activity and worsens acute liver injury during acetaminophen hepatotoxicity in mice.

Acetaminophen (N-Acetyl-p-Aminophenol or APAP)-induced hepatotoxicity is the most common cause of acute liver failure in the United States and Western Europe. Previous studies have shown that TGFß1 is elevated during APAP-induced hepatotoxicity and promotes liver injury by reducing liver regeneration while inducing hepatocyte senescence. At this time, little is known about the role of proteins that activate latent TGFß1 and their effects during APAP-induced hepatotoxicity. Thrombospondin-1 (TSP1) is a homotrimeric protein that can not only activate latent TGFß1 but can also interact with other proteins including Nrf2 to induce antioxidant signaling. The aim of the current study was to assess the role of thrombospondin-1 (TSP1) in both TGFß1 activation and its contribution to APAP-induced liver injury. C57Bl/6 mice or TSP1 null mice (TSP1-/-) were administered 300 mg/kg or 600 mg/kg of APAP. TGFß1 signaling, TSP1 expression, measures of hepatic injury, Nrf2 expression, measures of oxidative/nitrosative stress and GSH metabolism were assessed. The expression of TGFß1, TSP1 and phosphorylation of SMAD proteins increased in APAP-treated mice compared to controls. TSP1-/- mice had reduced TGFß1 expression and phosphorylation of SMAD proteins but increased liver injury. Hepatocyte cell death was increased in TSP1-/- mice and this was associated with decreased Nrf2 activity, decreased GSH levels and increased oxidative stress in comparison to wild-type C57Bl/6 mice. Together, these data demonstrate that elimination of TSP1 protein in APAP-treated mice reduces TGFß1 signaling but leads to increased liver injury by reducing Nrf2 expression and GSH activity, ultimately resulting in increased cell death.

Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor ß1.

Severe hepatic insults can lead to acute liver failure and hepatic encephalopathy (HE). Transforming growth factor ß1 (TGFß1) has been shown to contribute to HE during acute liver failure; however, TGFß1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGFß1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess TSP-1 during acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1-/-) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurologic decline, and molecular analyses of TSP-1 and TGFß1 signaling were performed. AOM-treated mice had increased TSP-1 and TGFß1 mRNA and protein expression in the liver. TSP-1-/- mice administered AOM had reduced liver injury as assessed by histology and serum transaminase levels compared with C57Bl/6 AOM-treated mice. TSP-1-/- mice treated with AOM had reduced TGFß1 signaling that was associated with less hepatic cell death as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cleaved caspase 3 expression. TSP-1-/- AOM-treated mice had a reduced rate of neurologic decline, less cerebral edema, and a decrease in microglia activation in comparison with C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGFß1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.