Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a \u3e80% reduction in COL1A1 mRNA, and a \u3e70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease

Clinical Diagnosis of Placenta Accreta and Clinicopathological Outcomes

Objective To investigate the association between the intraoperative diagnosis of placenta accreta at the time of cesarean hysterectomy and pathological diagnosis. Study Design This is a retrospective cohort study of all patients undergoing cesarean hysterectomy for suspected placenta accreta from 2000 to 2016 at Barnes-Jewish Hospital. The primary outcome was the presence of invasive placentation on the pathology report. We estimated predictive characteristics of clinical diagnosis of placenta accreta using pathological diagnosis as the correct diagnosis. Results There were 50 cesarean hysterectomies performed for suspected abnormal placentation from 2000 to 2016. Of these, 34 (68%) had a diagnosis of accreta preoperatively and 16 (32%) were diagnosed intraoperatively at the time of cesarean delivery. Two patients had no pathological evidence of invasion, corresponding to a false-positive rate of 4% (95% confidence interval [CI]: 0.5%, 13.8%) and a positive predictive value of 96% (95% CI: 86.3%, 99.5%). There were no differences in complications among patients diagnosed intraoperatively compared with those diagnosed preoperatively. Conclusion Most patients undergoing cesarean hysterectomy for placenta accreta do have this diagnosis confirmed on pathology. However, since the diagnosis of placenta accreta was made intraoperatively in nearly a third of cesarean hysterectomies, intraoperative vigilance is required as the need for cesarean hysterectomy may not be anticipated preoperatively

Three dimensional rotational angiography imaging of double aortic arch vascular ring

Three dimensional (3D) rotational angiography is a technique used increasingly for imaging in congenital heart disease. Here the use of this technique for imaging of double aortic arch vascular ring is described and the advantages of this modality. are discussed. 3D rotational angiography is an excellent tool for imaging of various vascular anomalies. It provides high quality accurate images through a quick and safe procedure.peer-reviewe

Large-scale features of Pliocene climate: results from the Pliocene Model Intercomparison Project

Climate and environments of the mid-Pliocene warm period (3.264 to 3.025 Ma) have been extensively studied. Whilst numerical models have shed light on the nature of climate at the time, uncertainties in their predictions have not been systematically examined. The Pliocene Model Intercomparison Project quantifies uncertainties in model outputs through a coordinated multi-model and multi-model/data intercomparison. Whilst commonalities in model outputs for the Pliocene are clearly evident, we show substantial variation in the sensitivity of models to the implementation of Pliocene boundary conditions. Models appear able to reproduce many regional changes in temperature reconstructed from geological proxies. However, data/model comparison highlights that models potentially underestimate polar amplification. To assert this conclusion with greater confidence, limitations in the time-averaged proxy data currently available must be addressed. Furthermore, sensitivity tests exploring the known unknowns in modelling Pliocene climate specifically relevant to the high latitudes are essential (e.g. palaeogeography, gateways, orbital forcing and trace gasses). Estimates of longer-term sensitivity to CO2 (also known as Earth System Sensitivity; ESS), support previous work suggesting that ESS is greater than Climate Sensitivity (CS), and suggest that the ratio of ESS to CS is between 1 and 2, with a "best" estimate of 1.5

Nova mutação nonsense (p.Y113X) no gene do receptor do hormônio do crescimento em um paciente brasileiro com síndrome de Laron

BACKGROUND: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. METHODS: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. RESULTS: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. CONCLUSION: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.INTRODUÇÃO: Até o momento, aproximadamente 60 diferentes mutações envolvendo o gene do receptor do GH (GHR) foram descritas em pacientes com a síndrome de insensibilidade ao GH (GHI). Neste artigo, descrevemos uma nova mutação nonsense do GHR. MÉTODOS: O paciente foi avaliado aos 6 anos de idade para baixa estatura associada ao fenótipo clínico da GHI. Níveis de GH, IGF-1 e GHBP foram determinados. Os produtos de PCR dos éxons 2-10 foram seqüenciados. RESULTADOS: O paciente apresentou níveis elevados de GH (26 µg/L), baixos de IGF-1 (22.5 ng/ml) e indetectáveis de GHBP. O seqüenciamento do éxon 5 do GHR revelou uma duplicação da adenina no nucleotídeo 338 da sequência de codificação do GHR (c.338dupA) em homozigose. CONCLUSÃO: Descrevemos uma nova mutação que causa um GHR truncado e uma perda da função do receptor devido à perda de aminoácidos compreendendo as regiões transmembrana e intracelular do receptor, levando a GHI.Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

The Evolution of Grocery Wholesaling and Grocery Wholesalers in Ireland and Britain since the 1930s

Studies of industry evolution are relatively scarce outside of industries defined by narrow technological bases. Studies of wholesaling are rarer still. These are curious features given that it is probable that service industries behave differently to manufacturing ones and that wholesaling is such a key function of many economies. This paper looks at the evolution of grocery wholesaling and grocery wholesalers in Ireland and Britain since 1930. It focuses on the processes and drivers of the wholesale industry. Similarities and differences between the two countries are discussed. Particular emphasis is placed on the role of government action as a triggering mechanism for change and on the role of trade associations and industry leaders in developing and following through on market and non-market strategies. The pathways of industry evolution identified differ from those seen in manufacturing. They therefore raise a number of issues for the development of understanding and conceptualisation in industry evolution studies

Predictive value of midtrimester universal cervical length screening based on parity

OBJECTIVES: To evaluate the effect of parity on performance characteristics of midtrimester cervical length (CL) in predicting spontaneous preterm birth (sPTB) before 37 weeks. METHODS: This was a retrospective cohort study of 13,508 women with no history of sPTB undergoing universal transvaginal CL screening at 17 to 23 weeks\u27 gestation from 2011 to 2016. Patients who declined screening or with unknown delivery outcomes were excluded. Areas under the receiver operator characteristic curves were used to assess and compare the predictive ability of CL screening for sPTB. The sensitivity, specificity, and positive and negative predictive values were estimated for specific CL cutoffs for prediction of sPTB. RESULTS: There were 20,100 patients, of whom 2087 (10%) declined screening and 4505 (22%) did not meet inclusion criteria. Of the remaining 13,508 patients, 43% were nulliparous. The incidence rates of sPTB were 6.5% in nulliparas and 4.9% in multiparas (P \u3c .001). The mean CLs were 39.9 mm in nulliparas and 41.8 mm in multiparas (P \u3c .001), and those of the first percentiles were 19.0 mm in nulliparas and 24.0 mm in multiparas. Cervical length was significantly more predictive of sPTB in nulliparas (area under the curve, 0.67; 95% confidence interval, 0.63-0.70; versus 0.61, 95% confidence interval, 0.57-0.63; P = .008). At CL cutoffs of 10, 15, 20, and 25 mm or less, the sensitivity was lower in multiparas, and the specificity was comparable between the groups. CONCLUSIONS: Midtrimester CL is less predictive of sPTB in multiparas compared to nulliparas. The poor predictive ability, especially in multiparas, calls into question the value of universal CL screening in this population

Effect of CPOE User Interface Design on User-Initiated Access to Educational and Patient Information during Clinical Care

Objective: Authors evaluated whether displaying context sensitive links to infrequently accessed educational materials and patient information via the user interface of an inpatient computerized care provider order entry (CPOE) system would affect access rates to the materials. Design: The CPOE of Vanderbilt University Hospital (VUH) included "baseline” clinical decision support advice for safety and quality. Authors augmented this with seven new primarily educational decision support features. A prospective, randomized, controlled trial compared clinicians' utilization rates for the new materials via two interfaces. Control subjects could access study-related decision support from a menu in the standard CPOE interface. Intervention subjects received active notification when study-related decision support was available through context sensitive, visibly highlighted, selectable hyperlinks. Measurements: Rates of opportunities to access and utilization of study-related decision support materials from April 1999 through March 2000 on seven VUH Internal Medicine wards. Results: During 4,466 intervention subject-days, there were 240,504 (53.9/subject-day) opportunities for study-related decision support, while during 3,397 control subject-days, there were 178,235 (52.5/subject-day) opportunities for such decision support, respectively (p = 0.11). Individual intervention subjects accessed the decision support features at least once on 3.8% of subject-days logged on (278 responses); controls accessed it at least once on 0.6% of subject-days (18 responses), with a response rate ratio adjusted for decision support frequency of 9.17 (95% confidence interval 4.6-18, p < 0.0005). On average, intervention subjects accessed study-related decision support materials once every 16 days individually and once every 1.26 days in aggregate. Conclusion: Highlighting availability of context-sensitive educational materials and patient information through visible hyperlinks significantly increased utilization rates for study-related decision support when compared to "standard” VUH CPOE methods, although absolute response rates were lo