Miracle-dz/UniFAR-FTUs huggingface dataset:
Medication Appropriateness at End of Life: A New Tool for Balancing Medicine and Communication for Optimal Outcomes—the BUILD Model

The BUILD model was created to provide a systematic framework for hospice clinicians to have important conversations with patients and families as well as facilitating useful conversations with interdisciplinary teammates. Although this article focuses on medication appropriateness and discontinuation of medications, this model can also be used when discussing prognosis, code status, goals of care, drug diversion, and when collaborating to develop a plan of care. When provided with a communication tool that is versatile, logical, and effective, hospice clinicians may use it, supporting improved patient care outcomes.
Quantitation of pretreatment serum interferon‐γ–inducible protein‐10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response

Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon‐γ–inducible protein‐10 (IP‐10) may also differentiate antiviral response. We evaluated IP‐10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP‐10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP‐10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP‐10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP‐10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP‐10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP‐10 had 64% SVR versus 24% with high IP‐10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP‐10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP‐10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP‐10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non‐CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;)
Hepatocyte nuclear factor‐4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A2 GXIIB

Hepatocyte nuclear factor‐4 alpha (HNF‐4α) is an important transcription factor governing the expression of genes involved in multiple metabolic pathways. Secreted phospholipase A2 GXIIB (PLA2GXIIB) is an atypical member of a class of secreted phospholipases A2. We establish in this study that PLA2GXIIB is an HNF‐4α target gene. We demonstrate that HNF‐4α binds to a response element on the PLA2GXIIB promoter. Moreover, HNF‐4α agonists induce PLA2GXIIB expression in human hepatocarcinoma cells. Importantly, PLA2GXIIB‐null mice accumulate triglyceride, cholesterol, and fatty acids in the liver and develop severe hepatosteatosis resembling some of the phenotypes of liver‐specific HNF‐4α–null mice. These defects are in part due to compromised hepatic very low‐density lipoprotein secretion. Finally, adenovirus‐mediated overexpression of HNF‐4α elevates serum triglyceride level in wild‐type but not PLA2GXIIB‐null mice. Conclusion: Collectively, these evidences suggest that HNF‐4α is a key physiological PLA2GXIIB transcriptional regulator and that PLA2GXIIB is a novel mediator of triglyceride metabolism in the liver. (HEPATOLOGY 2011;53:458‐466)
Interferência mútua entre atividade visual e atividade motora em jovens e idosos

Como o envelhecimento provoca dificuldade na capacidade de dividir a atencao, este estudo visou verificar, em jovens e idosos: (1) a eventual interferencia entre uma tarefa visual e uma motora; (2) se essa interferencia (caso exista) ocorre de forma diferente no desempenho de jovens e idosos; (3) se as tarefas propostas tem correlacao com testes validados, de sequencia alfanumerica (TMT) e de levantar e caminhar cronometrado (TLCC). A tarefa visual consistiu na verbalizacao do reconhecimento de duas figuras iguais ou diferentes apresentadas rapidamente. A tarefa motora consistiu na alternância de passos do chao a uma plataforma fixa de 10 cm de altura. As tarefas foram avaliadas isoladas (tarefa-simples) e associadas (tarefa-dupla) em dois grupos: 10 jovens (23±2,8 anos) e 10 idosos (68,8±8,6 anos). Na tarefa visual, os jovens fizeram menos erros que os idosos (p<0,001); nos dois grupos nao houve maior numero de erros na tarefa-simples quando comparada a tarefa-dupla. Na tarefa motora, os idosos tiveram pior desempenho na tarefa-dupla em relacao a tarefa-simples (p=0,009). Houve correlacao positiva entre o TMT e o numero de alternâncias de passos (p<0,05) e correlacao negativa entre o numero de alternâncias de passos e o TLCC (p<0,05). A tarefa motora nao interferiu na tarefa visual em jovens nem em idosos, mas a tarefa visual diminuiu a velocidade da tarefa motora dos idosos. A proposicao das tarefas sem atribuir primariedade a uma ou outra permitiu detectar essas interferencias.
Septum transversum‐derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver

The septum transversum mesenchyme (STM) signals to induce hepatogenesis from the foregut endoderm. Hepatic stellate cells (HSCs) are sinusoidal pericytes assumed to originate from the STM and participate in mesenchymal‐epithelial interaction in embryonic and adult livers. However, the developmental origin of HSCs remains elusive due to the lack of markers for STM and HSCs. We previously identified submesothelial cells (SubMCs) beneath mesothelial cells (MCs) as a potential precursor for HSCs in developing livers. In the present study, we reveal that both STM in embryonic day (E) 9.5 and MC/SubMCs in E12.5 share the expression of activated leukocyte cell adhesion molecule (Alcam), desmin, and Wilms tumor 1 homolog (Wt1). A cell lineage analysis using MesP1Cre/Rosa26lacZflox mice identifies the mesodermal origin of the STM, HSCs, and perivascular mesenchymal cells (PMCs). A conditional cell lineage analysis using the Wt1CreERT2 mice demonstrates that Wt1+ STM gives rise to MCs, SubMCs, HSCs, and PMCs during liver development. Furthermore, we find that Wt1+ MC/SubMCs migrate inward from the liver surface to generate HSCs and PMCs including portal fibroblasts, smooth muscle cells, and fibroblasts around the central veins. On the other hand, the Wt1+ STM and MC/SubMCs do not contribute to sinusoidal endothelial cells, Kupffer cells, and hepatoblasts. Conclusion: our results demonstrate that HSCs and PMCs are derived from MC/SubMCs, which are traced back to mesodermal STM during liver development. (HEPATOLOGY 2011;.)
The Genuair® inhaler: a novel, multidose dry powder inhaler

This article reviews the Genuair® inhaler, a novel, multidose, breath‐actuated dry powder inhaler. The inhaler design includes visual and acoustic feedback to reassure patients that they have taken their medication correctly, a dose indicator and a lock‐out mechanism to prevent the use of an empty inhaler. The inhaler has medium airflow resistance and uses an optimised dispersion system to ensure effective deagglomeration of the inhalation powder. In vitro studies have demonstrated that the inhaler delivers a reproducible aerodynamic aerosol quality and is reliable under various thermal and mechanical stress conditions. Further studies in vitro have demonstrated that the total emitted dose and fine particle dose are both consistent over a range of inhalation flows from 45 to 95 l/min, as well as being independent of inhalation volume (2 l vs. 4 l) and storage conditions. In healthy subjects, delivery of aclidinium bromide 200 μg via the inhaler achieved high lung deposition (approximately 30% of the metered dose). A further study has shown that patients with moderate or severe chronic obstructive pulmonary disease can generate sufficient inspiratory airflow through the inhaler to reliably inhale the full dose and reset the inhaler. The inhaler has been used to deliver aclidinium in many clinical trials and the available data indicate that it has high acceptability amongst patients.
Sleep, Recovery, and Athletic Performance: A Brief Review and Recommendations

ABSTRACT SLEEP HAS BEEN IDENTIFIED AS AN IMPORTANT FACTOR CONTRIBUTING TO OPTIMAL ATHLETIC PERFORMANCE. HOWEVER, THE PSYCHOSOCIOPHYSIOLOGICAL STRESSES PLACED ON ELITE ATHLETES MAY RESULT IN AN INABILITY TO GAIN APPROPRIATE SLEEP. IMPROVING AN ATHLETE'S SLEEP HYGIENE IS SEEN AS A KEY STRATEGY THAT COULD HAVE POWERFUL IMPLICATIONS FOR ATHLETIC PERFORMANCE. THEREFORE, THE PURPOSE OF THIS ARTICLE IS TO (A) OVERVIEW THE IMPACT OF SLEEP ON RECOVERY AND ATHLETIC PERFORMANCE; (B) OUTLINE SLEEP HYGIENE STRATEGIES; AND (C) PROVIDE SLEEP RECOMMENDATIONS FOR ATHLETES AND COACHES. THE SLEEP HYGIENE STRATEGIES PRESENTED IN THIS ARTICLE REPRESENT A PRACTICAL APPROACH TO IMPROVE SLEEP IN ELITE ATHLETES.
Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl-2 and caspase-3

Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target.
Human UDP-Glucuronosyltransferases: Effects of altered expression in breast and pancreatic cancer cell lines

Increased aerobic glycolysis and de novo lipid biosynthesis are common characteristics of invasive cancers. UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that in normal cells possess the ability to glucuronidate these lipids and speed their excretion; however, de-regulation of these enzymes in cancer cells can lead to an accumulation of bioactive lipids, which further fuels cancer progression. We hypothesize that UGT2B isoform expression is down-regulated in cancer cells and that exogenous re-introduction of these enzymes will reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. In this study, steady-state mRNA levels of UGT isoforms from the 2B family were measured using qPCR in 4 breast cancer and 5 pancreatic cancer cell lines. Expression plasmids for UGT2B isoforms known to glucuronidate cellular lipids, UGT2B4, 2B7, and 2B15 were transfected into MCF-7 and Panc-1 cells, and the cytotoxic effects of these enzymes were analyzed using trypan blue exclusion, annexin V/PI staining, TUNEL assays, and caspase-3 immunohistochemistry. There was a significant decrease in cell proliferation and a significant increase in the number of dead cells after transfection with each of the 3 UGT isoforms in both cell lines. Cellular lipids were also found to be significantly decreased after transfection. The results presented here support our hypothesis and emphasize the important role UGTs can play in cellular proliferation and lipid homeostasis. Evaluating the effect of UGT expression on the lipid levels in cancer cell lines can be relevant to understanding the complex regulation of cancer cells, identifying the roles of UGTs as “lipid-controllers” in cellular homeostasis, and illustrating their suitability as targets for future clinical therapy development.
Spo0B of Bacillus anthracis – a protein with pleiotropic functions

Spo0B is an important component of the phosphorelay signal transduction pathway, the pathway involved in the initiation of sporulation in Bacillus subtilis. Bioinformatic, phylogenetic and biochemical studies showed that Spo0B of Bacillus anthracis has evolved from citrate/malate kinases. During the course of evolution, Spo0B has retained the characteristic histidine kinase boxes H, N, F, G1 and G2, and has acquired nucleotide‐binding domains, Walker A and Walker B, of ATPases. Owing to the presence of these domains, autophosphorylation and ATPase activity was observed in Spo0B of B. anthracis. Mutational studies showed that among the six histidine residues, His13 of the H‐box is involved in the autophosphorylation activity of Spo0B, whereas Lys33 of the Walker A domain is associated with the ATPase activity of the protein. Thermodynamic and binding studies of the binding of Mg‐ATP to Spo0B using isothermal titration calorimetry (ITC) suggested that the binding is driven by favorable entropy changes and that the reaction is exothermic, with an apparent dissociation constant (Kd) equal to 0.02 mm. The value of the dissociation constant (Kd = 0.05 mm) determined by the intrinsic fluorescence of trytophan of Spo0B was similar to that obtained by ITC studies. The purified Spo0B of B. anthracis also showed nucleoside diphosphate kinase‐like activity of phosphate transfer from nucleoside triphosphate to nucleoside diphosphate. This is the first evidence for Spo0B of B. anthracis as an enzyme with histidine kinase and ATPase activities, which may have important roles to play in sporulation and pathogenesis.
Survey of Adolescent Views of Healthy Eating During Pregnancy

PurposeTo obtain baseline data about the food choices of pregnant adolescents, their knowledge about healthy eating, current eating habits, and how they feel they learn best. MethodsA 22-item survey was distributed to pregnant adolescents (n = 49, ages 15–19) who attended a teen-parenting program or prenatal clinic. Descriptive statistics were used for analysis of data. FindingsThe pregnant teenagers in this study reported that healthy eating was important to them. They ate three or more meals a day, but their snacks generally consisted of unhealthy food choices. They knew about food nutrition labels but did not always use those labels to make healthy food choices. Most adolescents were interested in exercise and stated that if they had access to a gym or someone to exercise with, they would exercise more often. Study participants reported they learned best by listening to information given to them by personnel in medical offices, clinics, and at school. Adolescents responded that their mothers did most of the grocery shopping and meal preparation. Conclusion and ImplicationsNurses are ideally positioned to provide prenatal nutrition education to pregnant adolescents, and to their families as well. Comprehensive nutritional education should focus on helping adolescents increase the amount of dairy products they consume and also on assisting them to interpret nutrition labels.
Ils vont bien… un an après

> Depuis la premiere publication [1] concernant l’essai clinique de therapie genique realise a l’hopital Necker (Paris, France), un certain nombre de questions restaient sans reponse. Elles concernaient differents champs tels que l’immunologie, l’hematopoiese, la clinique et la place de ce type d’essai dans la strategie therapeutique du deficit immunitaire combine severe (SCID-X1) lie a l’X (➜). Nous avons tente d’y repondre par l’analyse detaillee des caracteristiques des cinq premiers patients traites avec un recul de 1 a 2 ans et demi [2] et des patients traites par la suite.
Hodgkin lymphoma cell lines bind to platelets. Incubation with platelets induces CD15 and P-selectin dependent adhesion of the cell lines to Human Umbilical Vein Endothelial cells (HUVEC)

Hodgkin's lymphoma is believed to spread in an orderly fashion within the lymphatic compartment. In a minority of cases, after reaching the spleen, the neoplasm disseminates, reminiscent of metastasis. In the spleen, the Hodgkin-Reed-Sternberg tumor cells come across platelets in the blood vessels and mainly in the splenic red pulp. Based on this knowledge, we investigated the possibility of platelets inducing cell adhesion in Hodgkin's lymphoma cell lines. We showed that L428 and KMH-2 cells strongly adhere to thrombin-activated platelets. Cell adhesion to platelets is partially dependent on CD15 antigens (LewisX), mainly sialyl-CD15, and P-selectin. KMH-2, as compared to L428 cells, showed increased binding due to its differential high expression of the sialyl-CD15. As a consequence of incubation with platelets, KMH-2 cells also produced increased amounts of tumor necrosis factors α (TNFα) followed by enhanced binding to human vascular endothelial cells (HUVEC). Incubation of both cell lines with activated platelets also induced activation of AP-1 transcription complex. Our findings are consistent with the concept that platelets play a critical role in the dissemination of HRS cells in HL, predominantly in the spleen, by increasing cell adhesion and thus promoting their proliferative and migratory properties beyond the lymphatic system.
Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

ABSTRACT Background: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. Methods: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. Results: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio = 0.59, 95% CI:0.42-0.84; P = 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio = 0.79, 95%CI: 0.63-0.98; P = 0.03), and response rate (hazard ratio = 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. Conclusion: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumors.
Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)‐SMAD signaling pathway in mice

The bone morphogenetic protein 6 (BMP6)‐SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6‐SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6‐Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal‐regulated kinase 1 and 2 (Erk1/2) mitogen‐activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6‐Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo. (HEPATOLOGY 2011;)
Hepatic organic anion transporting polypeptide transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis

The role of organic anion transporting polypeptides (OATPs), particularly the members of OATP1B subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B subfamily, we have demonstrated previously that genetic ablation causes reduced hepatic clearance capacity for substrates. In this study, we focused on the physiological function of the hepatic OATP1B transporters. First, we studied the influence of the Oatp1b2 deletion on bile acid (BA) metabolism, showing that lack of the transporter results in a significantly reduced expression of Cyp7a1, the key enzyme of BA synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2−/− mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2−/− mice exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK) in knockout mice. We show that this phenotype is due to the loss of liver‐specific Oatp1b2‐mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR), including Cyp7a1 and Pepck but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers in which OATP1B1 expression was noted to be highly associated with TR target genes, especially for glucose facilitating transporter 2 (GLUT2). Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. Conclusion: Our findings reveal that OATP1B‐mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis. (HEPATOLOGY 2011;)