tbuckley/cabot-search huggingface dataset:
Intravascular Neutrophil Activation Due to Carbon Monoxide Poisoning
Authors: Stephen R. Thom, Veena M. Bhopale, Shih-Tsung Han, James M. Clark, Kevin R. Hardy
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: We hypothesized that platelet–neutrophil interactions occur as a result of acute carbon monoxide (CO) poisoning, and subsequent neutrophil activation triggers events that cause neurologic sequelae.Objectives: To identify platelet–neutrophil interactions and neutrophil activation in patients and in animal models, and to establish the association between these intravascular events and changes linked to CO-mediated neurologic sequelae in an animal model.Measurements and Main Results: Blood was obtained from 50 consecutive patients. Abnormalities were variable depending on the carboxyhemoglobin level at study admission and duration of CO exposure. Platelet–neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning. Among patients exposed to CO for over 3 h, flow cytometry scans of neutrophils revealed increased surface expression of CD18 and, in some groups, MPO on the cell surface. Animal models revealed consistent evidence of platelet–neutrophil aggregates, neutrophil activation and surface MPO, and plasma MPO elevation. MPO was deposited along the brain vascular lining and colocalized with nitrotyrosine. CO poisoning caused abnormalities in the charge pattern of myelin basic protein (MBP), changes linked to adaptive immunologic responses responsible for neurologic sequelae in this model. Changes did not occur in thrombocytopenic rats, those receiving tirofiban to inhibit platelet–neutrophil interactions, or those receiving l-nitroarginine methyl ester to inhibit nitric oxide synthesis. Alterations in MBP did not occur in CO-poisoned knockout mice lacking MPO.Conclusions: Acute CO poisoning causes intravascular neutrophil activation due to interactions with platelets. MPO liberated by neutrophils mediates perivascular oxidative stress, which is linked to immune-mediated neurologic sequelae.
RENEW 2055: 60 years old and counting
Authors: L. H. Clever
Journal: Journal of the Royal Society of Medicine (2005)

Greetings from a kindred spirit! You, dear reader in 2055, your colleagues, family, friends and neighbours are, I hope, so familiar with the services and programmes of RENEW that you take them for granted. In the late 20th century, however, RENEW was only a seed. It began as a not-for-profit enterprise to help people sustain or regain their enthusiasm, effectiveness, and purpose by giving them the wherewithal to renew themselves—and their relationships, organizations, and professions. If in 2055 you do take RENEW's services and programmes for granted you may find it hard to understand why its formative years were so difficult. In those days, many doctors were reluctant to acknowledge the personal challenges of our profession and were uneasy about trying something new. Fortunately, we pressed on. Why?

In the 20th century's last decade, times were tough for physicians, other health professionals, and their patients in the United States. Costs were high; opportunities for listening, learning, and teaching were scant; relationships were topsy-turvy, with internet-empowered patients firing questions and making demands. It was difficult for practitioners or professors to gain satisfaction, much less pleasure or even joy, from their life and work. Many worried that they were shortchanging their families, friends, and communities. Some became convinced that their own health suffered as professional pressures robbed them of the time and energy to do the things they counselled their patients to do—take exercise, read, write, play the zither, socialize, learn something. This was close to home—even my own home, because my husband and daughter are physicians. And I decided to try to help.

Colleagues and I launched RENEW first to offer health professionals services and programmes that would help us cope with the turbulence and competing imperatives of our commitments. Our inspiration was John W Gardner, PhD, a statesman-scholar who understood the unhappy consequences of unrelenting strain and inspired many with his books and speeches about renewal. John wrote, ‘the release of human possibilities within an ethical and moral framework [is] crucial to the flourishing of any society.’ My colleagues and I concluded that flourishing should be the goal. Flourishing is central to the sound practice of medicine: when health professionals overlook family and personal needs, they can become cynical, exhausted, hard on themselves, and hard on others.
Targeted Deletion of p53 in the Proximal Tubule Prevents Ischemic Renal Injury
Authors: Yuan Ying, Jinu Kim, Sherry N. Westphal, Kelly E. Long, Babu J. Padanilam
Journal: Journal of the American Society of Nephrology (2014)

The contribution of p53 to kidney dysfunction, inflammation, and tubular cell death, hallmark features of ischemic renal injury (IRI), remains undefined. Here, we studied the role of proximal tubule cell (PTC)-specific p53 activation on the short- and long-term consequences of renal ischemia/reperfusion injury in mice. After IRI, mice with PTC-specific deletion of p53 (p53 knockout [KO]) had diminished whole-kidney expression levels of p53 and its target genes, improved renal function, which was shown by decreased plasma levels of creatinine and BUN, and attenuated renal histologic damage, oxidative stress, and infiltration of neutrophils and macrophages compared with wild-type mice. Notably, necrotic cell death was attenuated in p53 KO ischemic kidneys as well as oxidant-injured p53-deficient primary PTCs and pifithrin-α–treated PTC lines. Reduced oxidative stress and diminished expression of PARP1 and Bax in p53 KO ischemic kidneys may account for the decreased necrosis. Apoptosis and expression of proapoptotic p53 targets, including Bid and Siva, were also significantly reduced, and cell cycle arrest at the G2/M phase was attenuated in p53 KO ischemic kidneys. Furthermore, IRI-induced activation of TGF-β and the long-term development of inflammation and interstitial fibrosis were significantly reduced in p53 KO mice. In conclusion, specific deletion of p53 in the PTC protects kidneys from functional and histologic deterioration after IRI by decreasing necrosis, apoptosis, and inflammation and modulates the long-term sequelae of IRI by preventing interstitial fibrogenesis.
Pilot Study of Spirituality and Mental Health in Twins
Authors: Ming T. Tsuang, Wesley M. Williams, John C. Simpson, Michael J. Lyons
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The goal of this study was to investigate associations between empirically defined dimensions of spirituality, personality variables, and psychiatric disorders in Vietnam era veterans. METHOD: One hundred pairs of male twins from the Vietnam Era Twin Registry were administered the self-report Spiritual Well-Being Scale and a pilot Index of Spiritual Involvement. Correlation analyses were supplemented with regression analyses that examined the relative influence of genetic and environmental factors on aspects of spirituality. RESULTS: Existential well-being was significantly associated with seven of 11 dimensions of personality and was significantly negatively associated with alcohol abuse or dependence and with two of three clusters of personality disorder symptoms. Associations between mental health variables and religious well-being or spiritual involvement were much more limited. CONCLUSIONS: Useful distinctions can be made between major dimensions of spirituality in studies of spirituality, religious coping, and mental health.
Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3α, Mip-3β, and Secondary Lymphoid Organ Chemokine
Authors: Akiko Iwasaki, Brian L. Kelsall
Journal: The Journal of Experimental Medicine (2000)

We describe the anatomical localization of three distinct dendritic cell (DC) subsets in the murine Peyer's patch (PP) and explore the role of chemokines in their recruitment. By two-color in situ immunofluorescence, CD11b+ myeloid DCs were determined to be present in the subepithelial dome (SED) region, whereas CD8α+ lymphoid DCs are present in the T cell–rich interfollicular region (IFR). DCs that lack expression of CD8α or CD11b (double negative) are present in both the SED and IFR. By in situ hybridization, macrophage inflammatory protein (MIP)-3α mRNA was dramatically expressed only by the follicle-associated epithelium overlying the SED, while its receptor, CCR6, was concentrated in the SED. In contrast, CCR7 was expressed predominantly in the IFR. Consistent with these findings, reverse transcriptase polymerase chain reaction analysis and in vitro chemotaxis assays using freshly isolated DCs revealed that CCR6 was functionally expressed only by DC subsets present in the SED, while all subsets expressed functional CCR7. Moreover, none of the splenic DC subsets migrated toward MIP-3α. These data support a distinct role for MIP-3α/CCR6 in recruitment of CD11b+ DCs toward the mucosal surfaces and for MIP-3β/CCR7 in attraction of CD8α+ DCs to the T cell regions. Finally, we demonstrated that all DC subsets expressed an immature phenotype when freshly isolated and maintained expression of subset markers upon maturation in vitro. In contrast, CCR7 expression by myeloid PP DCs was enhanced with maturation in vitro. In addition, this subset disappeared from the SED and appeared in the IFR after microbial stimulation in vivo, suggesting that immature myeloid SED DCs capture antigens and migrate to IFR to initiate T cell responses after mucosal microbial infections.
Evidence of Antiangiogenic and Antimetastatic Activities of the Recombinant Disintegrin Domain of Metargidin
Authors: Véronique Trochon-Joseph, Dominique Martel-Renoir, Lluis M. Mir, Annick Thomaïdis, Paule Opolon, Elisabeth Connault, Hong Li, Christophe Grenet, Françoise Fauvel-Lafève, Jeannette Soria, Chantal Legrand, Claudine Soria, Michel Perricaudet, He Lu
Journal: Cancer Research (2004)

Abstract Metargidin, a transmembrane protein of the adamalysin family, and integrins, e.g., α5β1 and αv, are preferentially expressed on endothelial cells on angiogenesis. Furthermore, metargidin interacts with these integrins via its disintegrin domain. In this study, recombinant human disintegrin domain (RDD) was produced in Escherichia coli by subcloning its cDNA into the pGEX-2T vector, and the effect of purified RDD on different steps of angiogenesis was evaluated. At concentrations of 2–10 μg/ml, RDD exhibited inhibitory activities in a variety of in vitro functional assays, including endothelial cell proliferation and adhesion on the integrin substrates fibronectin, vitronectin, and fibrinogen. RDD (10 μg/ml) totally abrogated endothelial cell migration and blocked most capillary formation in a three-dimensional fibrin gel. To test RDD efficacy in vivo, the RDD gene inserted into pBi vector containing a tetracycline-inducible promoter was electrotransferred into nude mouse muscle. RDD was successfully synthesized by muscle cells in vivo as shown by immunolabeling and Western blotting. In addition, 78% less MDA-MB-231 tumor growth, associated with strong inhibition of tumor angiogenesis, was observed in athymic mice bearing electrotransferred RDD. Moreover, in the presence of RDD, 74% fewer B16F10 melanoma lung metastases were found in C57BL/6 mice. Taken together, these results identified this RDD as a potent intrinsic inhibitor of angiogenesis, tumor growth, and metastasis, making it a promising tool for use in anticancer treatment.
Genomic analysis of small-cell lung carcinomas: Discovery of a candidate stratification biomarker for a Bcl-2 inhibitor
Authors: Gang Wang, Steve Tahir, Chris Tse, Rick Lesniewski, Dimitri Semizarov
Journal: Clinical Cancer Research (2006)

B81   The Bcl-2 family proteins are key regulators of apoptosis, whose overexpression has been identified in cancer and associated with chemoresistance. A small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w (ABT-737) has been discovered and shown to improve survival, cause regression of established tumours, and produce cures in mouse models of small cell lung carcinomas (SCLC). The identification of specific patient populations responsive to Bcl-2 family inhibitors would greatly enhance their clinical utility.Using 23 small cell lung cancer lines with a broad range of sensitivity to ABT-737, genome-wide comparative genomic hybridization (CGH) studies were performed to identify regions of genetic aberrations that are associated with efficacy. Using the Affymetrix 100K SNP genotyping arrays and an in-house bioinformatics tool, we identified gene copy number alterations that correlate with the sensitivity of the cell lines to ABT-737. A long region on the chromosome 18q was amplified in the sensitive, but not in the resistant lines. Among other genes, Bcl-2 was found to be moderately amplified in cell lines that were highly sensitive to ABT-737. We explored the clinical relevance of the 18q amplification by analyzing previously published CGH datasets for SCLC tumours and by examining the Bcl-2 copy number on SCLC tissue microarrays using FISH. The amplification was detected in a significant fraction of tumours, thus raising the possibility of patient stratification for the treatment with Bcl-2 inhibitors. This study illustrates our approach to early discovery of patient stratification biomarkers for oncology drug candidates.
Elucidation of Thioredoxin as a Molecular Target for Antitumor Quinols
Authors: Tracey D. Bradshaw, Charles S. Matthews, Jennifer Cookson, Eng-Hui Chew, Manish Shah, Kevin Bailey, Anne Monks, Erik Harris, Andrew D. Westwell, Geoffrey Wells, Charles A. Laughton, Malcolm F.G. Stevens
Journal: Cancer Research (2005)

Abstract Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI50 &amp;lt; 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G2-M cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (β-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 μmol/L) or 2 (500 nmol/L and 1 μmol/L) determined that of ≥10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated &amp;gt;3-fold. Furthermore, quinols 1 and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC50 &amp;lt; 6 μmol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.
Detection of enterovirus specific RNA sequences in muscle biopsy specimens from patients with adult onset myositis.
Authors: G E Yousef, D A Isenberg, J F Mowbray
Journal: Annals of the Rheumatic Diseases (1990)

A subgenomic cDNA probe with broad specificity for a range of enteroviruses was used to test by an in situ hybridisation technique for the presence of enterovirus specific genomic sequences in muscle biopsy samples obtained from patients with chronic adult myositis. Virus specific RNA sequences were detected in 6/13 (46%) patients with idiopathic polymyositis or dermatomyositis. Control samples obtained from an equal number of patients suffering from other muscle disorders were negative. A monoclonal antibody specific for an enterovirus group was used to probe for viral antigens by indirect immunoperoxidase staining; all biopsy samples from test and control groups were negative.
Tornado in a dish: Revealing the mechanisms of ventricular arrhythmias in engineered cardiac tissues
Authors: I EFIMOV, C RIPPLINGER
Journal: Cardiovascular Research (2005)

Ventricular tachycardia and fibrillation (VT/VF) are the leading, immediate causes of death in the developed world.Investigation of the mechanisms of VT/VF spans over a century and a half.However, despite a long and exciting history of discovery in the field, we are still asking the same questions posed by Carl J. Wiggers in 1940 [1]: ''As to the fundamental mechanisms of fibrillation we have plenty of theories, but none is universally accepted. . .we may note in passing that they all center around two ideas, viz., (a) that the impulses arise from centers, or pacemakers, or (b) that the condition is caused by the re-entry of impulses and the formation of circles of excitation.Each of these views, again, has two groups of exponents, viz., (a) those who believe that a single focus, or excitation ring, occurs, and (b) those who favor the idea that multiple foci, or numerous circus rings, are developed.''In addition to these fundamental questions, we can also ask: (a) Is VF neurogenic or myogenic in nature?(b) Is VF maintained by the ''mother rotor'' or ''multiple wavelet'' mechanism?(c) Is there a ''critical mass'' of VF?The initial discovery of VT/VF produced by ''faradisation'' in Carl Ludwig's laboratory [2] during studies of autonomic control of the heart led to the domination of the neurogenic theory of VF.Yet, subsequent studies of Vulpian [3] and MacWilliam [4] laid to rest the neurogenic theory.They put forward a myogenic theory of VF that remained dominant for over a century.The triumph of this theory was
Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy
Authors: M Sherman, E M Yoshida, M Deschenes, M Krajden, V G Bain, K Peltekian, F Anderson, K Kaita, S Simonyi, R Balshaw, S S Lee
Journal: Gut (2006)

<b>Background:</b> The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. <b>Aims:</b> We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. <b>Patients:</b> Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. <b>Methods:</b> Patients were retreated with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators’ discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (&lt;50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. <b>Results:</b> A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and relapsers were similar although more non-responders had genotype 1 infection (87% <i>v</i> 69%). Overall SVR rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. <b>Conclusions:</b> These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.
Retinitis pigmentosa and allied conditions today: a paradigm of translational research
Authors: Carmen Ayuso, Jose M Millan
Journal: Genome Medicine (2010)

Monogenic human retinal dystrophies are a group of disorders characterized by progressive loss of photoreceptor cells leading to visual handicap. Retinitis pigmentosa is a type of retinal dystrophy where degeneration of rod photoreceptors occurs at the early stages. At present, there are no available effective therapies to maintain or improve vision in patients affected with retinitis pigmentosa, but post-genomic studies are allowing the development of potential therapeutic approaches. This review summarizes current knowledge on genes that have been identified to be responsible for retinitis pigmentosa, the involvement of these genes in the different forms of the disorder, the role of the proteins encoded by these genes in retinal function, the utility of genotyping, and current efforts to develop novel therapies.
B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies
Authors: Daniel A Winer, Shawn Winer, Lei Shen, Persis P Wadia, Jason Yantha, Geoffrey Paltser, Hubert Tsui, Ping Wu, Matthew G Davidson, Michael N Alonso, Hwei X Leong, Alec Glassford, Maria Caimol, Justin A Kenkel, Thomas F Tedder, Tracey McLaughlin, David B Miklos, H-Michael Dosch, Edgar G Engleman
Journal: Nature Medicine (2011)
Lipotoxicity and Decreased Islet Graft Survival
Authors: Cristiane B. Leitão, Karina Bernetti, Thipaporn Tharavanij, Pablo Cure, Vincenzo Lauriola, Per-Olof Berggren, Camillo Ricordi, Rodolfo Alejandro
Journal: Diabetes Care (2009)

OBJECTIVE To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients. RESEARCH DESIGN AND METHODS Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis. RESULTS Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 +/- 6.1 vs. 61.3 +/- 6.6 months, P = 0.029, and VLDL: 41.5 +/- 5.7 vs. 62.8 +/- 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03-8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders. CONCLUSIONS Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.