The ADC team approach resulted in resolved to markedly improved symptoms in 73% of patients whose symptoms persisted despite seeing a single specialist prior to referral.
Transport into the nucleus is critical for regulation of gene transcription and other intranuclear events. Passage of molecules into the nucleus depends in part upon their size and the presence of appropriate targeting sequences. However, little is known about the effects of hormones or their second messengers on transport across the nuclear envelope. We used localized, two-photon activation of a photoactivatable green fluorescent protein to investigate whether hormones, via their second messengers, could alter nuclear permeability. Vasopressin and other hormones that increase cytosolic Ca 2؉ and activate protein kinase C increased permeability across the nuclear membrane of SKHep1 liver cells in a rapid unidirectional manner. An increase in cytosolic Ca 2؉ was both necessary and sufficient for this process. Furthermore, localized photorelease of caged Ca 2؉ near the nuclear envelope resulted in a local increase in nuclear permeability. Neither activation nor inhibition of protein kinase C affected nuclear permeability. These findings provide evidence that hormones linking to certain G protein-coupled receptors increase nuclear permeability via cytosolic Ca 2؉ . Short term regulation of nuclear permeability may provide a novel mechanism by which such hormones permit transcription factors and other regulatory molecules to enter the nucleus, thereby regulating gene transcription in target cells.The nuclear envelope represents a structural and functional barrier to passage between the nucleus and the cytosol. Regulation of the permeability of this barrier is one potential mechanism to control access to the nucleus for proteins that affect nuclear function, including transcription factors and various kinases and phosphatases. Nucleocytosolic passage generally occurs through the nuclear pore complex (1, 2), a 125-MDa membrane-spanning protein complex consisting of eight ion channels and a large central passage (3). Movement of molecules through the nuclear pore is restricted on the basis of size and the presence or absence of appropriate localization sequences. Studies using electron scanning microscopy (4), fluorescence recovery after photo-bleaching techniques (5), and microinjection of fluorescently labeled dextrans (6) have shown that molecules up to 40 -60 kDa in size can cross the nuclear envelope without a signaling sequence. Proteins less than 4 -10 kDa in size freely pass from cytosol to nucleus (6 -8), while intermediate sized proteins (19 -40 kDa) do not need a targeting sequence to cross the nuclear pore, but the permeability of the pore to such molecules may be modulated (6 -8). One factor that appears to regulate the permeability of the nuclear pore to proteins in this intermediate size range is the amount of Ca 2ϩ within the nuclear envelope (6 -9), although there is now conflicting evidence about this (5). Little is known about the role of cytosolic factors such as second messengers in the regulation of nuclear pore permeability.The spatial pattern of second messenger signals is important for how thes...
Objectives: The aim of the study was to validate and optimize a severity prediction model for acute pancreatitis (AP) and to examine blood urea nitrogen (BUN) level changes from admission as a severity predictor. Study Design: Patients from 2 hospitals were included for the validation model (Children’s Hospital of the King’s Daughters and Children’s National Hospital). Children’s Hospital of the King’s Daughters and Cincinnati Children’s Hospital Medical Center data were used for analysis of BUN at 24 to 48 hours. Results: The validation cohort included 73 patients; 22 (30%) with either severe or moderately severe AP, combined into the all severe AP (SAP) group. Patients with SAP had higher BUN ( P = 0.002) and lower albumin ( P = 0.005). Admission BUN was confirmed as a significant predictor ( P = 0.005) of SAP (area under the receiver operating characteristic [AUROC] 0.73, 95% confidence interval [CI] 0.60–0.86). Combining BUN ( P = 0.005) and albumin ( P = 0.004) resulted in better prediction for SAP (AUROC 0.83, 95% CI 0.72–0.94). A total of 176 AP patients were analyzed at 24–48 hours; 39 (22%) met criteria for SAP. Patients who developed SAP had a significantly higher BUN ( P < 0.001) after 24 hours. Elevated BUN levels within 24 to 48 hours were independently predictive of developing SAP (AUROC: 0.76, 95% CI: 0.66–0.85). Patients who developed SAP had a significantly smaller percentage decrease in BUN from admission to 24 to 48 hours ( P = 0.002). Conclusion: We externally validated the prior model with admission BUN levels and further optimized it by incorporating albumin. We also found that persistent elevation of BUN is associated with development of SAP. Our model can be used to risk stratify patients with AP on admission and again at 24 to 48 hours.
Purpose of review: Chronic cough is the most common presenting complaint in a pediatric aerodigestive clinic. The etiology of chronic cough is varied and often includes more than one organ system. This review aims to summarize the current literature for a multidisciplinary approach when evaluating a child with chronic cough. Recent findings: There is very little medical literature focused on a multidisciplinary approach to chronic cough. In the limited data available, multidisciplinary clinics have been shown to be more cost-efficient for the families of children with complex medical problems, and also increase the likelihood of successfully obtaining a diagnosis. Summary: There is no consensus in the literature on how to work-up a child with chronic cough presenting to an aerodigestive clinic. Current studies from these clinics have shown improved outcomes related to cost-effectiveness and identifying definitive diagnoses. Future studies evaluating clinical outcomes are necessary to help delineate the utility of testing routinely performed, and to demonstrate the impact of interventions from each specialty on quality of life and specific functional outcome measures.
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