tbuckley/cabot-search huggingface dataset:
Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients
Authors: Pleuni E. Hooijman, Albertus Beishuizen, Christian C. Witt, Monique C. de Waard, Armand R. J. Girbes, Angelique M. E. Spoelstra-de Man, Hans W. M. Niessen, Emmy Manders, Hieronymus W. H. van Hees, Charissa E. van den Brom, Vera Silderhuis, Michael W. Lawlor, Siegfried Labeit, Ger J. M. Stienen, Koen J. Hartemink, Marinus A. Paul, Leo M. A. Heunks, Coen A. C. Ottenheijm
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.Objectives: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin–proteasome pathway is activated in the diaphragm.Methods: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin–proteasome pathway in the development of contractile weakness during mechanical ventilation.Measurements and Main Results: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin–proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.Conclusions: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin–proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
Chronic Partial Occlusion of the Pulmonary Artery in Cats
Authors: ARTHUR L. BASSETT, HENRY GELBAND
Journal: Circulation Research (1973)

The relation of single cell electrical activity to generation of force was determined for myocardium during the development of hypertrophy induced by pressure loading. Transmembrane potentials and isometric active force at optimal length (P o ) were monitored in isolated right ventricular papillary muscles and trabeculae carneae after inducing chronic right ventricular outflow tract obstruction. Cats subjected to partial pulmonary artery occlusion or to sham operation were studied 1, 3, 7, 10, 21, and &gt; 90 days after surgery. Right ventricular muscles were stimulated at 30/min at optimal length in Tyrode's solution (36°C). Muscles from sham-operated and 1 day pressure-loaded hearts had electrical and mechanical properties similar to normal muscles. Right ventricular peak systolic and end-diastolic pressures were increased for 1 and 3 day pressure-loaded hearts; the percent of right ventricular water was increased for 3, 7, and 10 day pressure-loaded hearts. Muscles from 3 day pressure-loaded ventricles had significantly decreased P o , maximum rate of force development, time to peak force, and duration of contraction compared with normal muscles, and their action potential plateaus originated at more negative potentials (mean 24.7 mv for 11 muscles). The alteration in action potential configuration was less obvious in muscles studied 7 and 10 days after partial pulmonary artery occlusion and did not occur 21 and &gt; 90 days after pressure loading; however, P o and maximum rate of force development remained decreased, although time to peak force and duration of contraction returned to normal for preparations from 7, 10, 21, and &gt; 90 day pressure-loaded ventricles.
CFTR and differentiation markers expression in non-CF and delta F 508 homozygous CF nasal epithelium.
Authors: F Dupuit, N Kälin, S Brézillon, J Hinnrasky, B Tümmler, E Puchelle
Journal: Journal of Clinical Investigation (1995)

Human nasal polyps from non-CF and delta F 508 homozygous CF patients were used to compare the expression of CFTR and markers epithelial differentiation, such as cytokeratins (CK) and desmoplakins (DP), at the transcriptional and translational levels. mRNA expression was assessed by semiquantitative RT/PCR kinetic assays while the expression and distribution of proteins were evaluated by immunofluorescence analysis. In parallel, for each nasal tissue specimen, the importance of surface epithelium remodeling and inflammation was estimated after histological observations. Our results show that the steady-state levels of CFTR, CK13, CK18, CK18, CK14, or DP 1 mRNA transcripts in delta F 508 CF nasal polyps were not significantly different from those of non-CF tissues. A variability in the CFTR mRNA transcript level and in the pattern of CFTR immunolabeling has been observed between the different tissue samples. However, no relationship was found between the level of CFTR mRNA transcripts and the CFTR protein expression and distribution, either in the non-CF or in the CF group. The histological observations of non-CF and CF nasal polyp tissue indicated that the huge variations in the expression and distribution of the CFTR protein were associated with the variations in the degree of surface epithelium remodeling and inflammation in the lamina propria. A surface epithelium, showing a slight basal cell hyperplasia phenotype associated with diffuse inflammation, was mainly characterized by a CFTR protein distribution at the apex of ciliated cells in both non-CF and CF specimens. In contrast, in a remodeled surface epithelium associated with severe inflammation, CFTR protein presented either a diffuse distribution in the cytoplasm of ciliated cells, or was absent. These results suggest that abnormal expression and distribution of the CFTR protein of CF airways is not only caused by CFTR mutations. Airway surface epithelium remodeling and inflammation could play a critical role in the posttranscriptional and/or the posttranslational regulation of the CFTR protein expression in non-CF and CF airways.
An Unquiet Mind: A Memoir of Moods and Madness
Authors: Steven Miles
Journal: JAMA (1995)

Kay Redfield Jamison, a professor of psychiatry at Johns Hopkins, is touched with fire. She has made manic-depressive disorder the centerpiece of a remarkable clinical and academic career. She coauthored<i>Manic Depressive Illness</i>and a fascinating book,<i>Touched With Fire: Manic Depressive Illness and the Artistic Temperament</i>. She caps this progression from the clinical study of bipolar disease to delineating its cultural significance with this revealing monograph about her experience as a person who has manic-depressive illness. Like her other work, the writing is clear, often lyrical, and a pleasure to read. <i>An Unquiet Mind</i>opens two doors. It is a uniquely informed account of the experience of manic-depressive disorder. It is also an account of how a physician, her psychiatrists, and her departments handled the issues of professional competence for this sometimes and always potentially disabling illness. Dr Jamison depicts the personal experience of manic-depressive illness as a part
A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor.
Authors: D B Durand, M R Bush, J G Morgan, A Weiss, G R Crabtree
Journal: The Journal of Experimental Medicine (1987)

Using a transient transfection assay, we have defined the sequences required for the activation of the IL-2 gene in response to signals from the T cell antigen receptor. To do so we have transfected the human T cell line Jurkat with hybrid DNA constructs in which fragments from the IL-2 gene are linked to an indicator gene. The indicator gene product, as well as IL-2 production from the endogenous IL-2 gene were assayed after activation of the transfected Jurkat cells by various stimuli. We have demonstrated that a 275 bp fragment stretching from 52 to 326 bp upstream of the IL-2 gene transcription initiation site is required for expression of the linked indicator gene. This IL-2 gene fragment has several of the characteristics of a transcriptional enhancer element, in that it functions in both orientations and will enhance the expression from the promoter of an unrelated gene. Such enhancement occurred only after activation of Jurkat cells through the T cell antigen receptor. More specifically, this 275 bp fragment activated the expression of a linked gene after binding of a monoclonal antibody to the Jurkat T cell antigen receptor in the presence of PMA. In addition, calcium ionophore, which circumvents antigen receptor binding in T cell activation, induced the expression of the linked gene through this 275 bp sequence, in the presence of PMA. Finally, in a mutant Jurkat cell line lacking T3/antigen receptor complexes at the cell surface, no expression due to the IL-2 5' flanking region was seen after exposure to antibody to the T cell antigen receptor plus PMA or to PHA plus PMA. In contrast, calcium ionophore plus PMA did induce the expression of a linked gene through the IL-2 5' flanking region in the mutant Jurkat cell line. The responsiveness of the transfected hybrid genes containing the IL-2 regulatory region paralleled the expression of the endogenous IL-2 gene, as determined by IL-2 bioassays. We conclude that the 275 bp IL-2 sequence (-326 to -52 bp) is a target for the signal pathway originating at the T cell antigen receptor. Definition of this 275 bp target sequence should now permit the isolation of the molecules that bind to and activate the IL-2 gene.
Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection
Authors: Iwijn De Vlaminck, Hannah A. Valantine, Thomas M. Snyder, Calvin Strehl, Garrett Cohen, Helen Luikart, Norma F. Neff, Jennifer Okamoto, Daniel Bernstein, Dana Weisshaar, Stephen R. Quake, Kiran K. Khush
Journal: Science Translational Medicine (2014)

In a prospective cohort study of heart transplant recipients, sequencing-based quantification of donor-derived DNA in plasma of recipients noninvasively diagnosed transplant rejection.
Humoral and Cellular Sensitivity to Collagen in Type II Collagen-Induced Arthritis in Rats
Authors: David E. Trentham, Alexander S. Townes, Andrew H. Kang, John R. David
Journal: Journal of Clinical Investigation (1978)

We have recently described a new animal model of arthritis induced by intradermal injection of a distinct type of collagen found in cartilage (type II collagen). Since immunologic sensitivity to collagen could play a role in the pathogenesis of this type II collagen-induced arthritis in rats, the ability of purified types of native collagens to induce cellular and humoral responses was quantified by antigeninduced tritiated thymidine incorporation into lymphocytes by collagen and passive hemagglutination, respectively. Rats injected intradermally with native heterologous or homologous type II collagens in adjuvant developed type-specific cellular as well as humoral reactivity. Types I and III collagens were less immunogenic than was type II. The latter collagen induced brisk cellular and humoral responses that were equivalent whether complete Freund's adjuvant or incomplete Freund's adjuvant were employed. Both responses could be induced by native type II collagens modified by limited pepsin digestion, indicating that they are not attributable to determinants in the telopeptide regions of the molecule. Thus, these studies demonstrate the unique immunogenic as well as arthritogenic properties of the type II collagen molecule and indicate that both result from a helical conformation of its structurally distinct α-chains. Further, they suggest that type II collagen may, by humoral or cellular mechanisms, provoke or perpetuate inflammation in other arthritic diseases.
Proapoptotic effect of hepatitis C virus CORE protein in transiently transfected cells is enhanced by nuclear localization and is dependent on PKR activation
Authors: Stefano Realdon, Martina Gerotto, Francesca Dal Pero, Oriano Marin, Anna Granato, Giuseppe Basso, Maurizio Muraca, Alfredo Alberti
Journal: Journal of Hepatology (2003)
The mitochondria-independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib-mediated mcl-1 downregulation and mitochondrial membrane destabilization
Authors: Ansgar Brüning, Martina Rahmeh, Andrea Gingelmaier, Klaus Friese
Journal: Molecular Cancer (2010)

Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIV-infected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells. By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed. At a concentration of 9 μg/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 μg/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 μg/ml), but did not have additional detrimental effects on non-malignant bone marrow cells. The ability of nelfinavir to induce apoptosis in leukemia cells as a single agent in a mitochondria-independent manner might suggest it could be used as a second or third line of treatment for leukemia patients for whom standard mitochondria-directed treatment strategies have failed. Combination treatment with nelfinavir and sorafenib might further enhance the efficacy of nelfinavir even on chemo-resistant leukemia cells.
Blood Flow Remodels Growing Vasculature During Vascular Endothelial Growth Factor Gene Therapy and Determines Between Capillary Arterialization and Sprouting Angiogenesis
Authors: Tuomas T. Rissanen, Petra Korpisalo, Johanna E. Markkanen, Timo Liimatainen, Maija-Riitta Ordén, Ivana Kholová, Anna de Goede, Tommi Heikura, Olli H. Gröhn, Seppo Ylä-Herttuala
Journal: Circulation (2005)

Background— For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels. Methods and Results— Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment. Conclusions— This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.
The mental health of UK Gulf war veterans: phase 2 of a two phase cohort study
Authors: K. Ismail
Journal: BMJ (2002)

To examine the prevalence of psychiatric disorders in veterans of the Gulf war with or without unexplained physical disability (a proxy measure of ill health) and in similarly disabled veterans who had not been deployed to the Gulf war (non-Gulf veterans).Two phase cohort study.Current and ex-service UK military personnel.Phase 1 consisted of three randomly selected samples of Gulf veterans, veterans of the 1992-7 Bosnia peacekeeping mission, and UK military personnel not deployed to the Gulf war (Era veterans) who had completed a postal health questionnaire. Phase 2 consisted of randomly selected subsamples from phase 1 of Gulf veterans who reported physical disability (n=111) or who did not report disability (n=98) and of Bosnia (n=54) and Era (n=79) veterans who reported physical disability.Psychiatric disorders assessed by the schedule for clinical assessment in neuropsychiatry and classified by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.Only 24% (n=27) of the disabled Gulf veterans had a formal psychiatric disorder (depression, anxiety, or alcohol related disorder). The prevalence of psychiatric disorders in non-disabled Gulf veterans was 12%. Disability and psychiatric disorders were weakly associated in the Gulf group when confounding was adjusted for (adjusted odds ratio 2.4, 99% confidence interval 0.8 to 7.2, P=0.04). The prevalence of psychiatric disorders was similar in disabled non-Gulf veterans and disabled Gulf veterans ( 19% v 24%; 1.3, 0.5 to 3.4). All groups had rates for post-traumatic stress disorder of between 1% and 3%.Most disabled Gulf veterans do not have a formal psychiatric disorder. Post-traumatic stress disorder is not higher in Gulf veterans than in other veterans. Psychiatric disorders do not fully explain self reported ill health in Gulf veterans; alternative explanations for persistent ill health in Gulf veterans are needed.
Complement-human histocompatibility antigen haplotypes in C2 deficiency.
Authors: Z L Awdeh, D D Raum, D Glass, V Agnello, P H Schur, R B Johnston, E W Gelfand, M Ballow, E Yunis, C A Alper
Journal: Journal of Clinical Investigation (1981)

C4 allotyping 13 homozygous C2-deficient individuals demonstrated 23 of 25 haplotypes to be of the relatively rare type C4A4 B2. This is of the same magnitude as the association of C2Q0 with HLA-DW2/DR2.
Nepmucin, a novel HEV sialomucin, mediates L-selectin–dependent lymphocyte rolling and promotes lymphocyte adhesion under flow
Authors: Eiji Umemoto, Toshiyuki Tanaka, Hidenobu Kanda, Soojung Jin, Kazuo Tohya, Kazuhiro Otani, Takahiro Matsutani, Masanori Matsumoto, Yukihiko Ebisuno, Myoung Ho Jang, Minoru Fukuda, Takako Hirata, Masayuki Miyasaka
Journal: The Journal of Experimental Medicine (2006)

Lymphocyte trafficking to lymph nodes (LNs) is initiated by the interaction between lymphocyte L-selectin and certain sialomucins, collectively termed peripheral node addressin (PNAd), carrying specific carbohydrates expressed by LN high endothelial venules (HEVs). Here, we identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches [PPs]), that is expressed in LN HEVs but not detectable in PP HEVs at the protein level. Unlike conventional sialomucins, nepmucin contains a single V-type immunoglobulin (Ig) domain and a mucin-like domain. Using materials affinity-purified from LN lysates with soluble L-selectin, we found that two higher molecular weight species of nepmucin (75 and 95 kD) were decorated with oligosaccharides that bind L-selectin as well as an HEV-specific MECA-79 monoclonal antibody. Electron microscopic analysis showed that nepmucin accumulates in the extended luminal microvillus processes of LN HEVs. Upon appropriate glycosylation, nepmucin supported lymphocyte rolling via its mucin-like domain under physiological flow conditions. Furthermore, unlike most other sialomucins, nepmucin bound lymphocytes via its Ig domain, apparently independently of lymphocyte function–associated antigen 1 and very late antigen 4, and promoted shear-resistant lymphocyte binding in combination with intercellular adhesion molecule 1. Collectively, these results suggest that nepmucin may serve as a dual-functioning PNAd in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains.
Effects of psoralen plus ultraviolet A irradiation on cultured epidermal cells in vitro and patients with vitiligo in vivo
Authors: C-S. Wu, C-C.E. Lan, L-F. Wang, G-S. Chen, C-S. Wu, H-S. Yu
Journal: British Journal of Dermatology (2006)

Both psoralen plus ultraviolet (UV) A (PUVA) and narrowband UVB (NB-UVB) irradiation are effective treatments for vitiligo vulgaris. However, the mechanisms of PUVA and NB-UVB in repigmentation are not thoroughly clarified. Our previous results showed that NB-UVB irradiation directly promotes melanocyte (MC) migration and stimulates MC proliferation via keratinocytes (KCs).In the present study, we used NB-UVB as a reference for comparison to investigate the immediate effects of PUVA on MC proliferation and migration.Cultured MCs and KCs were treated with PUVA or irradiated with NB-UVB. The direct impact of PUVA treatment on MCs was assessed in terms of its effect on MC proliferation and migration. The indirect effect of PUVA treatment and NB-UVB irradiation on MC proliferation via KCs was also investigated. The activities of matrix metalloproteinase (MMP)-2 and MMP-9, known for their influence on cell migration, were evaluated in the PUVA-treated MC and KC supernatants. The concentrations of MC mitogens/growth factors in the PUVA-treated KC supernatants were also determined. In addition, the serum levels of MC mitogens/growth factors in healthy controls, in patients with active vitiligo and in patients with repigmenting vitiligo after PUVA treatment were determined to elucidate the mechanisms of how PUVA induces vitiligo repigmentation in vivo.Our results demonstrated that PUVA treatment did not significantly stimulate the release of MC mitogens/growth factors from KCs. The migration of MCs was also not enhanced after PUVA treatment. The expression of MMP-2 activity in supernatants derived from PUVA-treated MCs was significantly increased as compared with the control group. However, neither MMP-2 nor MMP-9 activity in KC supernatants was stimulated by PUVA treatment. In contrast to NB-UVB, immediate effects of PUVA on MC proliferation and migration were not observed in this study. Sera from patients with repigmenting vitiligo after PUVA treatment contained higher levels of basic fibroblast growth factor, stem cell factor and hepatocyte growth factor as compared with healthy controls and patients with active vitiligo.Our results indicate that in addition to immune suppression, PUVA treatment creates a favourable milieu for promoting the growth of MCs in patients with vitiligo instead of directly stimulating the regrowth of MCs. Based on our results, we propose that in the active stage of vitiligo, PUVA treatment is the therapy of choice to slow down the destruction of MCs and to create a favourable environment for MCs to survive. In the stable stage of vitiligo, NB-UVB irradiation should be used to stimulate the proliferation and migration of MCs directly.