The mortality rate within one year following surgical treatment of periprosthetic femoral fractures is high and is similar to that after treatment for hip fractures. Because revision arthroplasty for the treatment of type-B periprosthetic fractures was associated with a one-year mortality rate that was significantly less than that after surgical treatment with open reduction and internal fixation, in instances when either treatment option is feasible, revision arthroplasty may be the preferred option.

The D1 dopamine receptor subtype is expressed in the brain, kidney and lymphocytes. D1 receptor function has been extensively studied and the receptor has been shown to modulate a wide range of physiological functions and behaviors. The expression of D1 receptor is known to change during development, disease states and chronic treatment; however, the molecular mechanisms that mediate the changes in D1 receptor expression under these circumstances are not well understood. While previous studies have identified extracellular factors and signaling mechanisms regulating the transcription of D1 receptor gene, very little is known about other regulatory mechanisms that modulate the expression of the D1 receptor gene. Here we report that the D1 receptor is post-transcriptionally regulated during postnatal mouse brain development and in the mouse CAD catecholaminergic neuronal cell line. We demonstrate that this post-transcriptional regulation is mediated by a molecular mechanism involving noncoding RNA. We show that the 1277 bp 3′untranslated region of D1 receptor mRNA is necessary and sufficient for mediating the post-transcriptional regulation. Using deletion and site-directed mutagenesis approaches, we show that the D1 receptor post-transcriptional regulation is specifically mediated by microRNA miR-142-3p interacting with a single consensus binding site in the 1277 bp 3′untranslated region of D1 receptor mRNA. Inhibiting endogenous miR-142-3p in CAD cells increased endogenous D1 receptor protein expression levels. The increase in D1 receptor protein levels was biologically significant as it resulted in enhanced D1 receptor-mediated signaling, determined by measuring the activation of both, adenylate cyclase and, the dopamine- and cAMP-regulated phosphoprotein, DARPP-32. We also show that there is an inverse correlation between miR-142-3p levels and D1 receptor protein expression in the mouse brain during postnatal development. This is the first study to demonstrate that the post-transcriptional regulation of D1 receptor expression is mediated by microRNA-induced translational suppression.

Retrograde membrane trafficking from plasma membrane to the Golgi and endoplasmic reticulum affects intracellular protein dynamics underlying cell function. Here, we developed split-fluorescent toxin reporters that enable a quantitative, sensitive, and real-time single-cell flow cytometry assay for retrograde membrane transport.

Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

Epithelial cells lining mucosal surfaces distinctively express the inflammatory bowel disease risk gene INAVA. We previously found that INAVA has dual and competing functions: one at lateral membranes where it affects mucosal barrier function and the other in the cytosol where INAVA enhances IL-1β signal transduction and protein ubiquitination and forms puncta. We now find that IL-1β–induced INAVA puncta are biomolecular condensates that rapidly assemble and physiologically resolve. The condensates contain ubiquitin and the E3 ligase βTrCP2, and their formation correlates with amplified ubiquitination, suggesting function in regulation of cellular proteostasis. Accordingly, a small-molecule screen identified ROS inducers, proteasome inhibitors, and inhibitors of the protein folding chaperone HSP90 as potent agonists for INAVA condensate formation. Notably, inhibitors of the p38α and mTOR pathways enhanced resolution of the condensates, and inhibitors of the Rho–ROCK pathway induced INAVA’s competing function by recruiting INAVA to newly assembled intercellular junctions in cells where none existed before.

A 2-year-old Chinese boy was admitted to the hospital after 2 days of pallor and fatigue and 1 day of dark urine. There was no recent history of illness, although his mother reported a 1-week history of intermittent, subjective fevers. There was no history of recent travel, no history of recent trauma, no sick contacts, no pertinent family history, no changes in diet, and no medications. His past medical history was significant for self-limited nosebleeds, which had increased in frequency over the few days before admission. On examination, the patient was afebrile and tachycardic, with an oxygen saturation of 88% on room air. He was pale and tired-appearing on arrival. He was in no respiratory distress, and there was no hepatosplenomegaly or lymphadenopathy. His skin examination was notable for jaundice, but there were no bruises, petechiae, or rash. He was noted to pass cola-colored urine while in the hospital. His chest radiograph was normal. Laboratory evaluation revealed a normal serum electrolyte level and normal serum urea nitrogen and creatinine levels. A complete blood count (CBC) revealed the following: a white blood cell count of 20,700 per mL with normal differential, hemoglobin of 4.1 g/dL, hematocrit of 11.8%, a platelet count of 365 000 per mL, a mean corpuscular volume of 88.2 femtoliters, and a red cell distribution width of 20.5%. Question What Are the Current Recommendations for the Evaluation of Anemia in the Pediatric Population? Discussion Anemia is estimated to affect up to 20% of the American population during childhood. 1 It can be defined on the basis of age-and sex-specific percentile criteria for hemoglobin concentration. The Centers for Disease Control and Prevention, for example, uses the fifth percentile and below to define anemia, resulting in a lower limit of normal range of 11.0 to 11.9 g/dL for children under age 12 and 12.5 to 13.5 g/dL for children ages 12 to 18 years. 2 Reference ranges for neonates vary considerably on the basis of factors such as gestational age and day of life, although standardized reference values have been established. 3 The diagnostic approach to anemia combines a thorough history and physical examination with laboratory testing aimed at identifying which cell lines are affected, characterizing the patient' s erythrocytes, and differentiating between aplastic and consumptive processes. The CBC, which is used to confirm the presence of anemia, will also reveal whether the patient has abnormalities in the leukocyte or thrombocyte lines. Several acquired or inherited diseases can contribute to peripheral cytopenia, and many,

No abstract

Classically considered a disease of early childhood characterised by malabsorption and failure to thrive, coeliac disease is now recognised to arise in genetically susceptible individuals at any age. Although permissive HLA genotypes are the strongest predictor of coeliac disease, they are not sufficient. Several prospective cohort studies enrolling genetically at-risk infants have investigated the role of potential triggers of coeliac disease autoimmunity, such as timing of gluten introduction, viral infections and dietary patterns. Much less is known about triggers of coeliac disease in adulthood. Better understanding of factors leading to coeliac disease may be helpful in the management of those with potential coeliac disease (elevated serum celiac antibodies without villous atrophy in the small intestine), many of whom initiate a gluten-free diet without demonstration of villous atrophy. There are a range of clinical presentations of celiac disease in childhood and patterns of coeliac serology, including fluctuation and spontaneous reversion on a gluten-containing diet, vary.There is a current debate over best strategies to manage adults and children with potential coeliac disease to avoid over-treatment and under-treatment. Childhood and adolescence carry unique issues pertaining to the diagnosis and management of coeliac disease, and include nutrition and growth, rescreening, repeat biopsy, dietary adherence concerns and transition to adult care. In conclusion, while coeliac disease has similar pathogenesis and general clinical manifestations in paediatric and adult populations, diagnostic and management approaches need to adapt to the developmental stages.