tbuckley/cabot-search huggingface dataset:
Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1
Authors: Caroline Cheng, M. Noorderloos, Elza D. van Deel, Dennie Tempel, Wijnand den Dekker, Kim Wagtmans, Dirk J. Duncker, Miguel P. Soares, Jon D. Laman, Henricus J. Duckers
Journal: Circulation Research (2010)

Heme oxygenase (HO)1 is an important modulator of physiological function with cytoprotective properties. Although HO1 has previously been associated with an improved survival of the vascular allograft in rat models in response to pharmaceutical induction of HO1 the exact mechanism by which HO1 exerts it protective function remains to be elucidated.We sought to define the role of HO1 in dendritic cells (DCs) function that governs the alloimmune response underlying the development of transplantation associated vasculopathy.Loss of HO1 in DCs or by small interfering RNA silencing resulted in major histocompatibility complex class II (MHCII) upregulation by CIITA- driven transcriptional regulation and by STAT1 (signal transducers and activators of transcription 1) phosphorylation. As a result, increased MHCII alloantigen presentation by HO1(-/-) DCs directed the primary T-cell response preferentially toward a CD4(+) T-cell, rather than a CD8(+) T-cell reaction. In a murine model for transplantation arteriosclerosis, adoptive transfer of HO1(-/-) DCs before allograft transplantation was indeed associated with pronounced intragraft CD4(+) T-cell infiltration and increased IgG deposition, suggestive of an accelerated development of vasculopathy toward the chronic phase. The role of HO1 in DC-mediated T cell activation was further validated by inhibition of endogenous HO1 in allograft recipients. Inhibition of HO1 in DCs aggravated transplant arteriosclerosis development, by increasing intima hyperplasia, and by activation of a CD4(+) T cells allograft response, mediated by MHCII upregulation.These findings demonstrate that HO1 plays an important role in the genetic regulation of the vascular alloimmune response elicited by DCs.
Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis
Authors: Min Li, Manda Sai Krishnaveni, Changgong Li, Beiyun Zhou, Yiming Xing, Agnes Banfalvi, Aimin Li, Vincent Lombardi, Omid Akbari, Zea Borok, Parviz Minoo
Journal: Journal of Clinical Investigation (2010)

Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.
Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy
Authors: Kengo Kidokoro, Minoru Satoh, Keith M. Channon, Toyotaka Yada, Tamaki Sasaki, Naoki Kashihara
Journal: Journal of the American Society of Nephrology (2013)

In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2(+/Akita) diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2(+/Akita) mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.
Sentinel Lymphadenectomy Does Not Increase the Incidence of In-Transit Metastases in Primary Melanoma
Authors: John C. Kang, Leslie A. Wanek, Richard Essner, Mark B. Faries, Leland J. Foshag, Donald L. Morton
Journal: Journal of Clinical Oncology (2005)

Recent reports by European investigators suggest that sentinel lymphadenectomy (SLND), a mainstay of melanoma diagnosis and treatment planning, increases the risk of in-transit metastasis (ITM) and should be abandoned. This study compared the incidence of ITM after wide local excision (WLE), WLE plus SLND (SLND), or WLE plus elective lymphadenectomy (ELND) for primary melanoma.Review of our prospective database identified 4,412 patients who underwent WLE (n = 2,771), SLND (n = 1,016), or ELND (n = 625) for stage I/II melanoma (1971 through 2002). The incidence of ITM overall and as a first recurrence was examined before and after computerized prognostic matching of treatment groups. Intergroup statistical comparisons used chi(2) analysis and log-rank test.The incidence of ITM increased with Breslow depth, Clark level, and T stage. Although overall incidence of ITM was significantly higher (P = .0008) after ELND (6.56%) versus WLE (3.36%) or SLND (3.64%), the ELND group had higher risk primaries. Treatment groups matched by T stage (1,875 patients; 625 per group) or by age, sex, Breslow depth, and primary location (1,680 patients; 560 per group), showed no significant differences in ITM overall or as a first recurrence.There is no relationship between SLND and ITM. Recent reports to the contrary reflect analysis of significantly smaller cohorts not matched for confounding variables such as T stage. The phase III Multicenter Selective Lymphadenectomy Trial will definitively settle the issue; until then, use of SLND, the most accurate staging procedure for early-stage melanoma, should continue.
MHC class I molecules form ternary complexes with calnexin and TAP and undergo peptide-regulated interaction with TAP via their extracellular domains.
Authors: W K Suh, E K Mitchell, Y Yang, P A Peterson, G L Waneck, D B Williams
Journal: The Journal of Experimental Medicine (1996)

Newly assembled heavy chain-beta 2m heterodimers of class I histocompatibility molecules associate with the endoplasmic reticulum (ER) peptide transporter, TAP, and subsequently dissociate from TAP in parallel with their transport from the ER to the Golgi apparatus. It appears that TAP-associated class I molecules are waiting to bind appropriate peptides before they dissociate from TAP and leave the ER since binding of high affinity peptides to class I molecules in vitro leads to dissociation of TAP-class I complexes. In further support of this notion, we report that limiting peptide supply through inhibition of proteasome activities prolongs the association of mouse class I molecules with TAP and concomitantly slows their transport to the Golgi apparatus. By using a series of deletion mutants and hybrid class I molecules we demonstrate that the extracellular domains of class I molecules are sufficient for their peptide-regulated interaction with TAP. Furthermore, based on the inability of an alpha 3 domain-specific mAb to recognize TAP-class I complexes and the fact that a point mutant of the Dd molecule at residue 222 is unable to bind to TAP, it is likely that a major site of interaction with TAP resides in the membrane-proximal region of the heavy chain alpha 3 domain. Finally, we examined the relationship between the interaction of mouse heavy chain-beta 2m heterodimers with TAP and with the resident ER chaperone, calnexin. Most heterodimers that bound to TAP were found to associate simultaneously with calnexin. Upon delivery of peptide to class I molecules in permeabilized cells, dissociation from TAP was observed but the interaction with calnexin was largely maintained. Therefore, both TAP and calnexin may participate in the ER retention of peptide-deficient class I molecules. However, since release from calnexin occurs after dissociation from TAP, it appears that calnexin ultimately determines if a class I molecule is to be exported from the ER.
The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint
Authors: B. Ejbjerg, F. McQueen, M. Lassere, E. Haavardsholm, P. Conaghan, P. O'Connor, P. Bird, C. Peterfy, J. Edmonds, M. Szkudlarek, H. Genant, P. Emery, Mikkel Østergaard
Journal: Annals of the Rheumatic Diseases (2005)

This paper presents the wrist joint MR images of the EULAR–OMERACT rheumatoid arthritis MRI reference image atlas. Reference images for scoring synovitis, bone oedema, and bone erosions according to the OMERACT RA MRI scoring (RAMRIS) system are provided. All grades (0–3) of synovitis are illustrated in each of the three wrist joint areas defined in the scoring system—that is, the distal radioulnar joint, the radiocarpal joint, and the intercarpal-carpometacarpal joints. For reasons of feasibility, examples of bone abnormalities are limited to five selected bones: the radius, scaphoid, lunate, capitate, and a metacarpal base. In these bones, grades 0–3 of bone oedema are illustrated, and for bone erosion, grades 0–3 and examples of higher grades are presented. The presented reference images can be used to guide scoring of wrist joints according to the OMERACT RA MRI scoring system.
Acquired Immunodeficiency With Reversed T4/T8 Ratios in Infants Born to Promiscuous and Drug-Addicted Mothers
Authors: Arye Rubinstein, Marc Sicklick, Asha Gupta, Larry Bernstein, Norman Klein, Ethan Rubinstein, Ilya Spigland, Lazar Fruchter, Nathan Litman, Haesoon Lee, Melvin Hollander
Journal: JAMA (1983)

A new syndrome of acquired immunodeficiency has been identified in seven children who were small for gestational age at birth and subsequently have exhibited failure to thrive, lymphadenopathy, parotitis, hepatosplenomegaly, interstitial pneumonia, and recurrent infections. All have a profound cell-mediated immunodeficiency with reversed T4/T8 ratios. Six are hypergammaglobulinemic and one has low IgG levels. The mothers of five of the seven children are sexually promiscuous and/or drug addicts. Three mothers have an immunodeficiency similar to that found in their infants. One of them died at age 33 years with a diagnosis of acquired immunodeficiency syndrome. In five of the children and in three of their mothers, there is evidence of a persistent Epstein-Barr virus (EBV) infection. We speculate that a perinatal or in utero transmission of EBV can induce an "infectious immunodeficiency." The clinical, histopathologic, and immunologic features resemble those described in adult homosexuals and drug addicts.
Time to Attainment of Recovery From Borderline Personality Disorder and Stability of Recovery: A 10-year Prospective Follow-Up Study
Authors: Mary C. Zanarini, Frances R. Frankenburg, D. Bradford Reich, Garrett Fitzmaurice
Journal: American Journal of Psychiatry (2010)

The purposes of this study were to determine time to attainment of recovery from borderline personality disorder and to assess the stability of recovery.A total of 290 inpatients who met both DSM-III-R and Revised Diagnostic Interview for Borderlines criteria for borderline personality disorder were assessed during their index admission using a series of semistructured interviews and self-report measures. The same instruments were readministered every 2 years for 10 years.Over the study period, 50% of participants achieved recovery from borderline personality disorder, which was defined as remission of symptoms and having good social and vocational functioning during the previous 2 years. Overall, 93% of participants attained a remission of symptoms lasting at least 2 years, and 86% attained a sustained remission lasting at least 4 years. Of those who achieved recovery, 34% lost their recovery. Of those who achieved a 2-year remission of symptoms, 30% had a symptomatic recurrence, and of those who achieved a sustained remission, only 15% experienced a recurrence.Taken together, the results of this study suggest that recovery from borderline personality disorder, with both symptomatic remission and good psychosocial functioning, seems difficult for many patients to attain. The results also suggest that once attained, such a recovery is relatively stable over time.
Of Struldbruggs, sugar, and gatekeepers: a tale of our times
Authors: D. Kerr
Journal: BMJ (2003)

Socially isolated, depressed old patients most often end up on the diabetes wards after someone notices their blood sugar is low and all other specialists have lost interest 

At the beginning of November Gladys noticed a mild ache in the left side of her chest when she got up to go to the toilet in the middle of the night. The nursing home dialled 999 and she was whisked off to hospital. After six hours of processing in the emergency department, she ended up on the acute admission unit where, despite 72 hours of tests, no cause was found for her pain. Gladys was moved to the cardiology ward but again, despite a further battery of tests (including repeating earlier ones) no one could say for sure what caused her pain. Throughout, Gladys remained befuddled, relatively immobile, occasionally incontinent, and “uncooperative.” She didn't like taking the 16 prescribed tablets each morning. The medicine for the elderly team felt that attempting rehabilitation was inappropriate. Due to pressure of beds Gladys was transferred at midnight to an orthopaedic ward, but because of the need to free up the bed for the next day's waiting list initiative patient, she was moved to urology. After three days it was noted that her blood sugar at the time of admission was 15 mmol/l, so the bed manager felt it appropriate that Gladys should be transferred to the diabetic ward, which had two bays closed because of Norwalk virus. At some stage Gladys lost her specs and bottom set of dentures. She will be having turkey on the diabetes ward on Christmas day.

“Old age is not so bad when you consider the alternatives,” said Maurice Chevalier. It is difficult to share his optimism after completing a general medical ward round, particularly if you are a …
Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis
Authors: Amal Ephrem, Souleima Chamat, Catherine Miquel, Sylvain Fisson, Luc Mouthon, Giuseppina Caligiuri, Sandrine Delignat, Sriramulu Elluru, Jagadeesh Bayry, Sebastien Lacroix-Desmazes, José L. Cohen, Benoît L. Salomon, Michel D. Kazatchkine, Srini V. Kaveri, Namita Misra
Journal: Blood (2007)
The force-velocity relation and stepwise shortening in cardiac muscle.
Authors: D V Vassallo, G H Pollack
Journal: Circulation Research (1982)

A series of experiments was carried out to determine the effects of load variation on the character of stepwise shortening. We imposed afterloaded isotonic contractions on rat ventricular trabeculae, and measured the effect of load on pause duration, i.e., on the duration of the periods during which there was no sarcomere shortening. Sarcomere lengths were measured by optical diffraction. Increases of load brought about increases of pause duration; the relation was linear. The relation did not appear to depend on time during contraction, but did depend on sarcomere length: for a given load, pauses were longer at shorter sarcomere lengths. In a supplementary protocol in which we measured the dynamics of the central segment of the muscle during muscle isometric contraction, we found that the velocity of sarcomere shortening during the shortening step was approximately independent of load. These results provide a framework for interpretation of muscle force-velocity relations: diminished velocity at high load may be the result of increased pause durations.
Expression of EphA2 and Ephrin A-1 in Carcinoma of the Urinary Bladder
Authors: Shaji Abraham, Deborah W. Knapp, Liang Cheng, Paul W. Snyder, Suresh K. Mittal, Dinesh S. Bangari, Michael Kinch, Lan Wu, Jay Dhariwal, Sulma I. Mohammed
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The EphA2 receptor tyrosine kinase is believed to play a role in tumor growth and metastasis. The clinical significance of the expression of EphA2 was observed in breast, prostate, colon, skin, cervical, ovarian, and lung cancers. The purpose of this work was to determine the expression of EphA2 and its ligand, Ephrin A-1, and E-cadherin in carcinoma of the urinary bladder, and determine EphA2 as a new target for therapy in bladder cancer. Experimental Design: EphA2 mRNA and protein expression was investigated by reverse transcription-PCR and Western blot, respectively, in bladder cancer cell lines. In addition, the expression of EphA2, Ephrin A-1, and E-cadherin in tissues from patients with different stages of urinary bladder cancer was determined by immunohistochemistry. Furthermore, the ability of Ephrin A-1 to inhibit growth of bladder cancer cells was also investigated using an adenoviral delivery system. Results: Western blot analysis showed high EphA2 expression in TCCSUP, T24, and UMUC-3 cell lines. In tissues, the staining intensity of EphA2 was less in normal urothelium but increased greatly in advancing stages of urothelial carcinoma (P &amp;lt; 0.05). Similarly, the staining intensity of Ephrin A-1 was low in normal tissues and high in cancerous tissues, but it was similar across the various stages of urothelial carcinoma (Ta-T4). E-cadherin immunoreactivity decreased in urothelial cancer. Association of EphA2 and Ephrin A-1 expression was found to be significant between Ta stage and T1-T2 (P &amp;lt; 0.04) and Ta and T3-T4 stages (P &amp;lt; 0.0001). Adenovirus delivery of Ephrin A-1 inhibited proliferation of TCCSUP cells. Conclusion: EphA2 may serve as a novel target for bladder cancer therapy.
Natural Variation in Arabidopsis lyrata Vernalization Requirement Conferred by a FRIGIDA Indel Polymorphism
Authors: H. Kuittinen, A. Niittyvuopio, P. Rinne, O. Savolainen
Journal: Molecular Biology and Evolution (2007)

Species share homologous genes to a large extent, but it is not yet known to what degree the same loci have been targets for natural selection in different species. Natural variation in flowering time is determined to a large degree by 2 genes, FLOWERING LOCUS C and FRIGIDA, in Arabidopsis thaliana. Here, we examine whether FRIGIDA has a role in differences in flowering time between and within natural populations of Arabidopsis lyrata, a close outcrossing perennial relative of A. thaliana. We found 2 FRIGIDA sequence variants producing potentially functional proteins but with a length difference of 14 amino acids. These variants conferred a 15-day difference in flowering time in an association experiment in 2 Scandinavian populations. The difference in flowering time between alleles was confirmed with transformation to A. thaliana. Because the north European late-flowering populations harbor both late- and early sequence variants at intermediate frequencies and the late-flowering variant is most frequent in the southern early flowering European population, other genetic factors must be responsible for the flowering time differences between the populations. The length polymorphism occurs at high frequencies also in several North American populations. The occurrence of functional variants at intermediate frequencies in several populations suggests that the variation may be maintained by balancing selection. This is in contrast to A. thaliana, where independent loss-of-function mutations at the FRIGIDA gene are responsible for differences between populations and local adaptation.
Functional and structural studies of ileal reservoirs used for continent urostomy and ileostomy.
Authors: B M Philipson, N G Kock, R Jagenburg, C Ahren, L Norlen, J W Robinson, H Menge
Journal: Gut (1983)

<h3>Abstract</h3> <h3>Motivation</h3> DisGeNET-RDF makes available knowledge on the genetic basis of human diseases in the Semantic Web (SW). Gene-disease associations (GDAs) and their provenance metadata are published as human-readable and machine-processable web resources. The information on GDAs included in DisGeNET-RDF is interlinked to other biomedical databases to support the development of bioinformatics approaches for translational research through evidence-based exploitation of a rich and fully interconnected Linked Open Data (LOD). <h3>Availability</h3> http://rdf.disgenet.org/ <h3>Contact</h3> support@disgenet.org
Prognostic trees to aid prognosis in patients with cutaneous malignant melanoma
Authors: T. C Aitchison, J. M Sirel, D. C Watt, R. M MacKie, f. t. S. M. Group
Journal: BMJ (1995)

<h3>Abstract</h3> <b>Objectives</b>: To design user friendly guides to prognosis for patients who have had invasive primary cutaneous malignant melanomas surgically excised. <b>Design</b>: Adaptation of the classification tree method was used to derive prognostic trees for four different subgroups of malignant melanoma patients in whom known and possible prognostic variables interacted in different ways. <b>Setting</b>: Scotland. <b>Subjects</b>: Statistical modelling for prognostic trees was based on 1978 patients whose primary malignant melanoma was first diagnosed in 1979-86 for whom five year follow up and all relevant clinical pathological data were available. The resultant model was validated with 300 patients first diagnosed in 1987 for whom the same information was available. <b>Main outcome measures</b>: Actual and predicted rate of survival after diagnosis of primary cutaneous malignant melanoma. <b>Results</b>: The four subgroups of patients were men and women with ulcerated and non-ulcerated cutaneous primary melanomas. Validation of the model showed excellent agreement between actual status of patients in the relevant subgroups and their status as predicted by the model. <b>Conclusions</b>: The prognostic trees are simple to use and give more accurate prognosis for individual patients than is currently available from tumour thickness alone.