tbuckley/cabot-search huggingface dataset:
Epithelial-mesenchymal transition: potential role in obliterative bronchiolitis?
Authors: B. C Willis, Z. Borok
Journal: Thorax (2009)

Lung transplantation remains the only viable option for many patients suffering from a variety of progressive or intractable end-stage lung diseases. Despite significant advances in the prevention of early graft rejection, ischaemia-reperfusion injury and acute management of lung transplant recipients, significant challenges remain in the chronic management of patients after lung transplantation.1 In this issue of Thorax , Borthwick and colleagues2 provide intriguing new evidence that implicates the airway epithelium directly in the pathogenesis of bronchiolitis obliterans syndrome (BOS), the most significant factor in determining long-term lung graft survival ( see page 770 ). As discussed in the study, the pathological lesion of BOS is obliterative bronchiolitis (OB), which recently has been postulated to be at least partially a disease of aberrant epithelial repair processes.3 Borthwick and colleagues provide evidence that epithelial to mesenchymal transition (EMT), a process whereby epithelial cells undergo a complete lineage transition to become fibroblasts and/or myofibroblasts, may underlie the dysfunctional airway repair processes that lead to OB. This study, and others like it, attempt to redefine traditional paradigms regarding normal airway epithelial biology and disease pathogenesis, and have the potential to lead to entirely new therapeutic avenues for previously untreatable disease processes such as BOS.

OB is characterised by initial inflammation of the small airways followed by airway remodelling, aberrant epithelial regeneration and repair, proliferation of fibroblasts and myofibroblasts, deposition of extracellular matrix (ECM) and eventual airway obstruction.4 The initial inflammatory response is the result of an allogeneic immune response initiated against donor antigens in the graft endothelial and airway epithelial cells. This response characteristically generates antigen-specific graft-infiltrating destructive lymphocytes. The lymphocytes facilitate activation of macrophages and a variety of other inflammatory cells, with resultant …
Diabetic Charcot Neuroarthropathy of the Knee: Conservative Treatment Options as Alternatives to Surgery
Authors: Ulrich Illgner, Jaap van Netten, Carolin Droste, Klaas Postema, Thomas Meiners, Hans H. Wetz
Journal: Diabetes Care (2014)

In contrast to the well-known Charcot neuroarthropathy (CN) of the foot, CN of the knee is hardly recognized. In a literature search, we only found five articles on total knee arthroplasty for Charcot joints (1–5). We did not find a single article dealing with alternative treatment options or the general clinical course of this disease.

We started our study because we saw two young patients with CN of knee within 2 months in our clinic. We reviewed all patients’ reports who had been treated in our clinic for CN of the foot ( N = 281) from 1998 to 2010. Written consent was obtained as required, and all demands of the Declaration of Helsinki were fulfilled.

We found three patients with CN of the knee (all female; patient A: 25 years …
The electronic patient record in primary care--regression or progression? A cross sectional study
Authors: J. Hippisley-Cox
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objectives</b> To determine whether paperless medical records contained less information than paper based medical records and whether that information was harder to retrieve. <b>Design</b> Cross sectional study with review of medical records and interviews with general practitioners. <b>Setting</b> 25 general practices in Trent region. <b>Participants</b> 53 British general practitioners (25 using paperless records and 28 using paper based records) who each provided records of 10 consultations. <b>Main outcome measures</b> Content of a sample of records and doctor recall of consultations for which paperless or paper based records had been made. <b>Results</b> Compared with paper based records, more paperless records were fully understandable (89.2% <i>v</i> 69.9%, P=0.0001) and fully legible (100% <i>v</i> 64.3%, P &lt; 0.0001). Paperless records were significantly more likely to have at least one diagnosis recorded (48.2% <i>v</i> 33.2%, P=0.05), to record that advice had been given (23.7% vs 10.7%, P=0.017), and, when a referral had been made, were more likely to contain details of the specialty (77.4% <i>v</i> 59.5%, P=0.03). When a prescription had been issued, paperless records were more likely to specify the drug dose (86.6% <i>v</i> 66.2%, P=0.005). Paperless records contained significantly more words, abbreviations, and symbols (P &lt; 0.01 for all). At doctor interview, there was no difference between the groups for the proportion of patients or consultations that could be recalled. Doctors using paperless records were able to recall more advice given to patients (38.6% <i>v</i> 26.8%, P=0.03). <b>Conclusion</b> We found no evidence to support our hypotheses that paperless records would be truncated and contain more local abbreviations; and that the absence of writing would decrease subsequent recall. Conversely we found that the paperless records compared favourably with manual records.
Maternal and Birth Chracterestics Are Associated with Infant Gut Microbial Composition
Authors: Christine Cole Johnson, Suzanne Havstad, Edward M. Zoratti, Kei Fujimura, Alexandra R. Sitarik, Haejin Kim, Andrea Cassidy-Bushrow, Kevin Bobbitt, Nicholas W. Lukacs, Kimberley J. Woodcroft, Homer A. Boushey, Dennis R. Ownby, Ganesa R. Wegienka, Albert M. Levin, Susan V. Lynch
Journal: Journal of Allergy and Clinical Immunology (2015)
The need for personalised medicine for rheumatoid arthritis
Authors: J. D. Isaacs, G. Ferraccioli
Journal: Annals of the Rheumatic Diseases (2010)

An expanding range of biological therapies is available for patients with rheumatoid arthritis. Clinical trials and real-life experience demonstrate significant interpatient heterogeneity in efficacy as well as important adverse effects of these treatments. In order to maximise their benefit:risk ratios and to minimise later joint damage, we need to define predictors of response and, ideally, of adverse effects for each of these drugs. There is huge interest in this field of 'personalised medicine', which should allow us to optimally match patient with treatment, providing the parallel benefit of reduced treatment costs. In this short article the current state of the art for licensed biological therapies is summarised. There have been some noteworthy discoveries but the challenge is now to design studies to confirm and validate these findings while also devising large, potentially international, collaborations to identify additional, robust biomarkers that predict outcome.
Fibroblast growth factor 21 protects the heart from oxidative stress
Authors: Anna Planavila, Ibon Redondo-Angulo, Francesc Ribas, Gloria Garrabou, Jordi Casademont, Marta Giralt, Francesc Villarroya
Journal: Cardiovascular Research (2014)

Oxidative stress mediated by reactive oxygen species (ROS) plays a striking role in the pathogenesis of heart failure, and antioxidants have been shown to attenuate cardiac remodelling in experimental models of cardiac damage. We recently showed that fibroblast growth factor 21 (Fgf21) is produced by the heart and exerts protective effects, preventing cardiac hypertrophy development. The aim of the study was to determine the effects of Fgf21 during oxidative stress signalling in the heart. Fgf21 treatment in cardiomyocytes in culture induced the expression of genes encoding proteins involved in antioxidative pathways, including mitochondrial uncoupling proteins (Ucp2 and Ucp3) and superoxide dismutase-2 (Sod2) and reduced ROS production. In keeping with this, expression of antioxidant genes in response to lipopolysaccharide (LPS)-induced stimulation of pro-inflammatory pathways or isoproterenol-induced cardiac hypertrophy in the heart was reduced in Fgf21-null mice. Moreover, we found that Fgf21 is expressed in and released by cardiomyocytes in response to LPS, and its expression is under the control of the Sirt1 (sirtuin-1) pathway. This Fgf21 released by cardiomyocytes acts in an autocrine manner to protect cells against oxidative stress. Finally, failing human hearts showed up-regulation of Fgf21, Ucp3, and Sod2, confirming the association between Fgf21 induction and the control of cardiac oxidative stress pathways. Our data indicate that Fgf21 regulates genes involved in antioxidant pathways in an autocrine manner, thus preventing ROS production in cardiac cells. Therefore, Fgf21 acts as an antioxidant factor in the heart, preventing induction of pro-oxidative pathways by inflammatory or hypertrophic conditions.
Coinfection of hepatitis C virus in patients with chronic hepatitis B infection
Authors: Shinjiro Sato, Shigetoshi Fujiyama, Motohiko Tanaka, Kunio Yamasaki, Izumi Kuramoto, Shin-ichi Kawano, Tatsuo Sato, Kyosuke Mizuno, Saneo Nonaka
Journal: Journal of Hepatology (1994)
Methotrexate plus prednisone in patients with relapsing idiopathic retroperitoneal fibrosis
Authors: Federico Alberici, Alessandra Palmisano, Maria L Urban, Federica Maritati, Elena Oliva, Lucio Manenti, Stefania Ferretti, Rocco Cobelli, Carlo Buzio, Augusto Vaglio
Journal: Annals of the Rheumatic Diseases (2013)

Secondary (functional) mitral regurgitation (SMR) most commonly arises secondary to left ventricular (LV) dilation/dysfunction. The concept of disproportionately severe SMR was proposed to help explain the different results of two randomised trials of transcatheter edge-to-edge mitral valve repair (TEER) versus medical therapy. This concept is based on the fact that effective regurgitant orifice area (EROA) depends on LV end-diastolic volume (LVEDV), ejection fraction, regurgitant fraction and the velocity-time integral of SMR. This review focuses on the haemodynamic framework underlying the concept and the myths and misconceptions arising from it. Each component of EROA/LVEDV is prone to measurement error which can result in misclassification of individual patients. Moreover, EROA is typically measured at peak systole rather than its mean value over the duration of MR. This can result in physiologically impossible values of EROA or regurgitant volume. Although the EROA/LVEDV ratio (1) emphasises that grading MR severity needs to consider LV size and function and (2) helps explain the different outcomes between COAPT and MITRAFR, there are important factors that are not included. Among these are left atrial compliance, LV pressure and ejection fraction, pulmonary hypertension, right ventricular function and tricuspid regurgitation. Because medical therapy can reduce LV volumes and improve both LV function and SMR severity, the key to patient selection is forced titration of neurohormonal antagonists to the target doses that have been proven in clinical trials (along with cardiac resynchronisation when appropriate). Patients who continue to have symptomatic severe SMR after doing so should be considered for TEER.
Thy-1 and T-Cell Receptor Antigen Expression in Mycosis Fungoides and Benign Inflammatory Dermatoses
Authors: D. P. Fivenson, L. A. Rheins, J. J. Nordlund, M. Pomaranski, M. C. Douglass, E. A. Krull
Journal: JNCI Journal of the National Cancer Institute (1991)

We have studied human Thy-1 and T-cell receptor (TCR) antigen expression in mycosis fungoides and benign inflammatory dermatoses. The study included 24 biopsy specimens from 21 patients with mycosis fungoides (nine patch stage from eight patients, 13 plaque stage from 11 patients, and two tumor stage from two patients), six specimens from five patients with premycotic parapsoriasis (pre-mycosis fungoides), three specimens from three patients with lichen planus, 11 specimens from 11 patients with lupus erythematosus, 13 specimens from 13 patients with dermatitis, six specimens from six patients with drug eruptions, nine normal skin specimens from nine subjects, and three specimens from three patients with small plaque (benign) parapsoriasis. Immunoperoxidase studies using the avidin-biotin complex technique on serial frozen sections were performed. Primary antibodies were anti-human Thy-1, anti-alpha heterodimer of the TCR, anti-beta heterodimer of the TCR, and anti-delta heterodimer of the TCR. An extensive dendritic network of Thy-1+ cells was seen in all cases of mycosis fungoides. Epidermotropic cells were Thy-1 negative, and Thy-1 was expressed perivascularly in normal individuals and patients as previously reported. Epidermal gamma/delta cells were seen only in mycosis fungoides, where up to 60% of the epidermal lymphocytes expressed this TCR. The increased numbers of Thy-1 and gamma/delta T cells in mycosis fungoides were statistically significant when compared with normal skin or benign inflammatory dermatoses. The role of these dendritic dermal Thy-1+ cells and epidermal gamma/delta T cells in mycosis fungoides is unclear. The significant numbers of these potentially immunomodulating cells that were seen suggest that they are involved in the pathogenesis of mycosis fungoides.
High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia
Authors: Susan O'Brien, Gary Schiller, John Lister, Lloyd Damon, Stuart Goldberg, Walter Aulitzky, Dina Ben-Yehuda, Wendy Stock, Steven Coutre, Dan Douer, Leonard T. Heffner, Melissa Larson, Karen Seiter, Scott Smith, Sarit Assouline, Philip Kuriakose, Lori Maness, Arnon Nagler, Jacob Rowe, Markus Schaich, Ofer Shpilberg, Karen Yee, Guenter Schmieder, Jeffrey A. Silverman, Deborah Thomas, Steven R. Deitcher, Hagop Kantarjian
Journal: Journal of Clinical Oncology (2012)

Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT).Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi).The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%).High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.
Cytomegalovirus associated neonatal pneumonia and Wilson-Mikity syndrome: a causal relationship?
Authors: F Reiterer, HJ Dornbusch, B Urlesberger, P Reittner, R Fotter, M Zach, H Popper, W Muller
Journal: European Respiratory Journal (1999)

Lung injury caused by intrauterine inflammation has recently been strongly implicated in the pathogenesis of Wilson-Mikity syndrome (WMS). This article supports this theory by suggesting a causative role of intrauterine cytomegalovirus (CMV) infection for the development of WMS. A male premature infant, born at 33 weeks of gestational age, developed chronic lung disease compatible with WMS and diagnostic evaluation was positive for CMV infection. High-resolution computed tomography scan and lung histology revealed typical features of WMS in association with signs of interstitial pneumonia. CMV was found in urine, breastmilk, bronchoalveolar lavage material and lung tissue from open lung biopsy. Follow-up after treatment with ganciclovir and steroids showed resolving lung disease at the age of 6, 10 and 16 months, with lung function signs of mild obstruction. Assuming that a chance coexistence of cytomegalovirus pneumonia and Wilson-Mikity syndrome is rather unlikely, it is possible that intrauterine cytomegalovirus infection caused a pattern of lung injury consistent with Wilson-Mikity syndrome. Further cases of Wilson-Mikity syndrome should be investigated as to a possible role of congenital infection.
Combined PTEN and p27kip1 Protein Expression Patterns Are Associated with Obesity and Prognosis in Endometrial Carcinomas
Authors: Athanassios Dellas, Gernot Jundt, Gideon Sartorius, Mischa Schneider, Holger Moch
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and p27kip1 proteins are key players of the Akt pathway, which is nutritionally regulated by insulin receptor signaling and influenced by estrogens. In this study, the prognostic relevance of the PTEN/p27kip1 protein expression in endometrial carcinoma in relationship to the body mass index (BMI) was determined. Experimental Design: BMI and prognosis of 452 surgically treated patients with endometrial carcinoma were correlated with histologic subtype, International Federation of Gynecology and Obstetrics (FIGO) stage, and differentiation grade. The expression of PTEN and p27kip1 was examined in 257 tumors by immunohistochemistry using a tissue microarray approach. Results: Lack of PTEN was observed in 136 of 257 (53%) tumors and absence of p27kip1 expression was observed in 106 of 225 (47%) tumors. Absence of both proteins was significantly associated with well-differentiated tumors [PTEN (P &amp;lt; 0.02) and p27kip1 (P &amp;lt; 0.009)]. Differentiation grade, tumor stage, and histologic type were independent of an increased BMI. Importantly, tumors of obese women expressed significantly less PTEN (P &amp;lt; 0.008) and less p27kip1 (P &amp;lt; 0.01) than tumors from nonobese patients. Combined absence of both PTEN and p27kip1 expression characterized a group of 75 (32%) tumors with favorable clinical outcome, particularly in the FIGO stages I and II (P = 0.003) of obese patients. Cox regression analysis revealed that PTEN/p27kip1 phenotype, FIGO stage, and histologic grade were independent predictors of prognosis in endometrioid endometrial carcinoma. Conclusions: Inactivation of PTEN/p27kip1 proteins is a specific feature in the progression of endometrial carcinoma in obese patients. The phenotype of the combined loss of PTEN/p27kip1 protein expression in obese patients is associated with a significantly better prognosis in endometrioid endometrial carcinoma.
Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents.
Authors: V A Maltsev, A M Wobus, J Rohwedel, M Bader, J Hescheler
Journal: Circulation Research (1994)

Cardiomyocytes differentiated in vitro from pluripotent embryonic stem (ES) cells of line D3 via embryo-like aggregates (embryoid bodies) were characterized by the whole-cell patch-clamp technique during the entire differentiation period. Spontaneously contracting cardiomyocytes were enzymatically isolated by collagenase from embryoid body outgrowths of early, intermediate, and terminal differentiation stages. The early differentiated cardiomyocytes exhibited an outwardly rectifying, transient K+ current sensitive to 4-aminopyridine and an inward Ca2+ current but no Na+ current. The Ca2+ current showed all features of L-type Ca2+ current, being highly sensitive to 1,4-dihydropyridines but not to omega-conotoxin. Cardiomyocytes of intermediate stage were characterized by the additional expression of cardiac-specific Na+ current, the delayed K+ current, and If current. Terminally differentiated cardiomyocytes expressed a Ca2+ channel density about three times higher than that of early stage. In addition, two types of inwardly rectifying K+ currents (IK1 and IK,Ach) and the ATP-modulated K+ current were found. During cardiomyocyte differentiation, several distinct cell populations could be distinguished by their sets of ionic channels and typical action potentials presumably representing cardiac tissues with properties of sinus node, atrium, and ventricle. Reverse transcription polymerase chain reaction revealed the transcription of alpha- and beta-cardiac myosin heavy chain (MHC) genes synchronously with the first spontaneous contractions. Transcription of embryonic skeletal MHC gene at intermediate and terminal differentiation stages correlated with the expression of Na+ channels. The selective expression of alpha-cardiac MHC gene in ES cell-derived cardiomyocytes was demonstrated after ES cell transfection of the LacZ construct driven by the alpha-cardiac MHC promoter region followed by ES cell differentiation and beta-galactosidase staining. In conclusion, our data demonstrate that ES cell-derived cardiomyocytes represent a unique model to investigate the early cardiac development and permit pharmacological/toxicological studies in vitro.
Melanoma cells constitutively release an anchor-positive soluble form of protectin (sCD59) that retains functional activities in homologous complement-mediated cytotoxicity.
Authors: L I Brasoveanu, E Fonsatti, A Visintin, M Pavlovic, I Cattarossi, F Colizzi, A Gasparollo, S Coral, V Horejsi, M Altomonte, M Maio
Journal: Journal of Clinical Investigation (1997)

Protectin (CD59), a glycosylphosphatidylinositol-anchored cell membrane glycoprotein, is differentially expressed on melanocytic cells and represents the main restriction factor of C-mediated lysis of melanoma cells. In this study, we report that CD59-positive melanoma cells constitutively release a soluble form of CD59 (sCD59), and that its levels directly correlate (r = 0.926; P < 0.05) with the amount of membrane-bound CD59. SDS-PAGE analysis showed that the molecular components of sCD59 are similar to those of cellular CD59 expressed by melanoma cells. Melanoma-released sCD59 is anchor positive since it inserts into cell membranes of homologous cells that transiently increase their expression of CD59. Moreover, sCD59 is functional: it blocks the binding of the anti-CD59 mAb YTH53.1 to melanoma cells and reverses its effects on C-mediated lysis. In fact, preincubation of mAb YTH53.1 with scalar doses of conditioned media of CD59-positive but not of CD59-negative melanoma cells reduced significantly (P < 0.05), and in a dose-dependent fashion, the enhancement of C-mediated lysis of anti-GD3-sensitized melanoma cells induced by the masking of cellular CD59 by mAb YTH53.1. Altogether, these data demonstrate that CD59-positive human melanoma cells release a soluble form of CD59 that is structurally similar to cellular CD59, retains its anchoring ability, is functional, and may impair the effectiveness of clinical approaches to humoral immunotherapy for human melanoma.