tbuckley/cabot-search huggingface dataset:
Cytokine profiles during clinical high-flux dialysis
Authors: M P Grooteman, M J Nubé, M R Daha, J Van Limbeek, M van Deuren, M Schoorl, P M Bet, A J Van Houte
Journal: Journal of the American Society of Nephrology (1997)

Secretion of cytokines by monocytes has been implicated in the pathogenesis of dialysis-related morbidity. Cytokine generation is presumed to take place in two steps: induction of mRNA transcription for cytokines by C5a and direct membrane contact, followed by lipopolysaccharide (LPS)-induced translation of mRNA (priming/second signal theory, Kidney Int 37: 85-93, 1990). However, the in vitro conditions on which this theory was based differed markedly from clinical dialysis. To test this postulate for routine hemodialysis, 13 patients were studied cross-over with high-flux cuprammonium (CU), cellulose triacetate (CTA), and polysulfon dialyzers, using standard bicarbonate dialysate, as well as CTA with filtered dialysate (fCTA). Besides leukocytes, C3a, C5a, and limulus amebocyte lysate reactivity, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, IL-1RA, soluble TNF receptors, and IL-1 beta mRNA were assessed. Only during dialysis with CU did C5a increase significantly (561 to 8185 ng/ml, P < 0.001). Endotoxin content of standard bicarbonate was higher than filtered dialysate (median, 24.3 and < 5 pg/ml respectively, P = 0.002), whereas limulus amebocyte lysate reactivity was not detected in the blood, except in the case of CU. TNF-alpha levels were elevated before, and remained stable during, dialysis, independent of the modality used. IL-1 beta, IL-6, and mRNA coding for IL-1 beta could not be demonstrated. IL-1RA and soluble TNF receptors (p55/p75) were markedly elevated compared with normal control subjects, but showed no differences between fCTA and CTA. To summarize, no evidence was found for production and release of cytokines by monocytes during clinical high-flux bicarbonate hemodialysis, neither with complement-activating membranes nor with unfiltered dialysate. Therefore, this study sheds some doubt on the relevance of the "priming/second signal" theory for clinical practice. The data presented suggest that reluctance to prescribe the use of high-flux dialyzers, as advocated in many reports, may not be warranted.
Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma
Authors: A. F. Behndig, N. Larsson, J. L. Brown, N. Stenfors, R. Helleday, S. T. Duggan, R. E. Dove, S. J. Wilson, T. Sandstrom, F. J. Kelly, I. S. Mudway, A. Blomberg
Journal: Thorax (2010)

<h3>Background</h3> Exposure to traffic-derived air pollutants, particularly diesel emissions, has been associated with adverse health effects, predominantly in individuals with pre-existing respiratory disease. Here the hypothesis that this heightened sensitivity reflects an augmentation of the transient inflammatory response previously reported in healthy adults exposed to diesel exhaust is examined. <h3>Methods</h3> 32 subjects with asthma (mild to moderate severity) and 23 healthy controls were exposed in a double-blinded crossover control fashion to both filtered air and diesel exhaust (100 μg/m<sup>3</sup> PM<sub>10</sub>) for 2 h. Airway inflammation was assessed by bronchoscopy 18 h postexposure. In addition, lung function, fraction of exhaled nitric oxide and bronchial reactivity to metacholine were examined in the subjects with asthma. <h3>Results</h3> In healthy control subjects a significant increase in submucosal neutrophils (p=0.004) was observed following the diesel challenge. Significant increases in neutrophil numbers (p=0.01), and in the concentrations of interleukin 6 (p=0.03) and myeloperoxidase (p=0.04), were also seen in bronchial wash after diesel, relative to the control air challenge. No evidence of enhanced airway inflammation was observed in the subjects with asthma following the diesel exposure. <h3>Conclusions</h3> Exposure to diesel exhaust at concentrations consistent with roadside levels elicited an acute and active neutrophilic inflammation in the airways of healthy subjects. This response was absent in subjects with asthma, as was evidence supporting a worsening of allergic airway inflammation.
Adoptive transfer of genetically engineered WT1-specific cytotoxic T lymphocytes does not induce renal injury
Authors: Hiroaki Asai, Hiroshi Fujiwara, Sohei Kitazawa, Naoto Kobayashi, Toshiki Ochi, Yukihiro Miyazaki, Fumihiro Ochi, Yoshiki Akatsuka, Sachiko Okamoto, Junichi Mineno, Kiyotaka Kuzushima, Hiroaki Ikeda, Hiroshi Shiku, Masaki Yasukawa
Journal: Journal of Hematology & Oncology (2014)

Because WT1 is expressed in leukemia cells, the development of cancer immunotherapy targeting WT1 has been an attractive translational research topic. However, concern of this therapy still remains, since WT1 is abundantly expressed in renal glomerular podocytes. In the present study, we clearly showed that WT1-specific cytotoxic T lymphocytes (CTLs) certainly exerted cytotoxicity against podocytes in vitro; however, they did not damage podocytes in vivo. This might be due to the anatomical localization of podocytes, being structurally separated from circulating CTLs in glomerular capillaries by an exceptionally thick basement membrane.
Reply: Is Warfarin the Right Anticoagulant in Idiopathic Pulmonary Fibrosis?
Authors: Imre Noth, Mitchell Olman
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

From the Authors:

We thank Drs. Bendstrup and Hilberg for their comments regarding the IPFnet ACE trial examining the use of warfarin in idiopathic pulmonary fibrosis (IPF), and agree with their premise for the need for further investigation of anticoagulant therapy in IPF (1).

We agree that the ACE study addresses the use of only warfarin in IPF. Importantly, there are several differences between ACE and the previous study examining the utility of anticoagulation in IPF by Kubo and coworkers (2). In the prior study, much less physiologically impaired patients with IPF were enrolled at hospitalization and placed on warfarin and prednisolone in combination, as opposed to warfarin alone. In fact, the number of subjects on both agents in ACE was very small. Furthermore, dalteparin, a low-molecular-weight heparin, was added during subsequent hospitalizations for acute exacerbation events. By allowing sicker patients in ACE, we both enhanced event rates, which was the objective, but may not have allowed sufficient time for a treatment effect to occur in altering the course of fibrosis.

There is a plethora of evidence demonstrating antifibrotic effects of anticoagulants, both dependent and independent of their anticoagulant actions (3). Factor VII activity has been demonstrated to be elevated in patients with interstitial lung disease, and specifically in IPF (3). Also recently demonstrated, factor VIIa stimulates proliferation of human lung fibroblasts and extracellular matrix in a PAR-2–dependent manner. This effect is factor Xa and thrombin independent (4). Additionally shown after ACE’s inception is that increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury (5). Furthermore, evidence supports a protective role for protein C, a vitamin K–dependent anticoagulant protein, on the endothelial cell barrier function in acute lung injury (6). This growing body of evidence supports the concept that anticoagulants targeting specific coagulation factors or their “fibrosis-signaling” receptors may exert antifibrotic effects independent of their anticoagulant activities.

Heparin shares anticoagulant action with warfarin, but its coagulation factor targets only partially overlap with that of warfarin. Furthermore, different heparin size fractions, and biochemical modifications, differ in their potencies, anticoagulant targets (such as thrombin or Factor X), and in their antiinflammatory and antiproliferative capacities (7–9). There is much evidence in vitro and in vivo to suggest that all anticoagulants are not equal with respect to their antifibrotic therapeutic potential. Thus, we agree that the compelling basic science and animal model observations would provide a solid foundation upon which to implement additional trials of “anti-coagulants” in IPF. In conclusion, we have answered the question of the utility of warfarin in progressive IPF, but many questions remain.
Loss of the VEGF164 and VEGF188 Isoforms Impairs Postnatal Glomerular Angiogenesis and Renal Arteriogenesis in Mice
Authors: Virginie Mattot, Lieve Moons, Florea Lupu, Daniel Chernavvsky, R. Ariel Gómez, Désiré Collen, Peter Carmeliet
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Vascular endothelial growth factor (VEGF) is transcribed in the VEGF120, VEGF164, or VEGF188 isoforms, which differ in receptor binding, matrix association, and angiogenic activity. This vascular growth factor has been implicated in the development of the renal vasculature, but the role of the distinct VEGF isoforms remains unknown. In the present report, renal angiogenesis and arteriogenesis were studied in VEGF120/120 mice, expressing only the short VEGF120 isoform. In VEGF120/120 mice, ingrowth and survival of capillaries in glomeruli, remodeling of peritubular capillaries, vascular coverage by pericytes, and branching of renal arteries were all severely impaired, causing abnormal glomerular filtration and impairing renal function. The arterial branching defect might be related to a reduced expression of renin, a presumed renal arterial branching factor. Glomerulosclerosis and tubular dilation possibly resulted from renal ischemia caused by vascular defects. Thus, VEGF164 and VEGF188 not only mediate angiogenesis, but they also play an essential role in renal branching arteriogenesis.
Analysis of speckled fluorescent antinuclear antibody test antisera using electrofocused nuclear antigens.
Authors: T B Okarma, J A Krueger, H R Holman
Journal: Journal of Clinical Investigation (1982)

Antibodies to different components of the extractable nuclear antigen (ENA) have been thought to be serological markers for clinical subsets of rheumatic diseases. However, incomplete characterization and standardization of antigenic components such as ribonucleoprotein (RNP), Sm, and SS-B (Ha), and the multiplicity of autoantibodies produced by different patients have confounded correlations between autoantibody specificity and disease subsets. This study describes the preparative separation of the antigens Sm, RNP, and Ss-B (Ha) by electrofocusing and their use in a rocket electrophoretic assay that in one step identifies and quantifies the multiple reactivities of patient sera exhibiting the speckled FANA pattern. Preparative electrofocusing generates milligram quantities of these antigens with retention of their immunologic and biochemical characteristics, facilitating further study of their biological properties and relationships to disease subsets.
Changing sulphasalazine to methotrexate does not improve the 2-year outcomes of the initial single DMARD treatment in early rheumatoid arthritis: subanalysis of the FIN-RACo trial
Authors: Vappu Marianna Rantalaiho, Hannu Kautiainen, Markku Korpela, Pekka J Hannonen, Marjatta Leirisalo-Repo, Timo Möttönen
Journal: Annals of the Rheumatic Diseases (2013)

The current treatment of rheumatoid arthritis (RA) aims at early and sustained remission.1 However, the opinions on how to reach this target vary. The European guideline recommends the use of initial methotrexate (MTX), and if that fails, adding a biologic. A combination of disease modifying antirheumatic drugs (DMARDs) is not seen as an option as initial therapy or as the next step in patients with active RA failing MTX.2 Others have, however, included combination DMARDs in the first and second line treatment recommendations,3 ,4 and the Finns, thanks to the encouraging results and comprehensive national participation in the FIN-RACo trial,5 even propose triple DMARD combination as the initial treatment in active early RA.6 Direct comparisons between combination therapy and single MTX have been lacking; until recently, the tREACH trial fulfilled this gap by confirming the superiority of triple combination compared with single MTX in early RA.7

The FIN-RACo trial proved that the initial triple DMARD combination (MTX, sulphasalazine (SASP) and hydroxychloroquine) is superior to single DMARD therapy, started with SASP, which, however, could be …
Points: Oral temperature and hypothermia
Authors: E L. Lloyd
Journal: BMJ (1979)

A N Bamji (14 April, p 973) with great interest.We were medical students resident in separate Dublin hospitals in 1966.At this time McIlroy appeared at the casualty department of the Royal City of Dublin Hospital complaining of chest pain.One of us (JRN) was connecting him to an ECG machine which required to be earthed.Unfortunately, this was not done and the patient obviously experienced an electric shock.He leapt from the trolley and, putting his finger over his tracheostomy, confirmed in no uncertain terms that this was the case.He took his own discharge.Later that evening this somewhat ruffled student called at the Adelaide Hospital three kilometres or so away.There CED was found to be examining McIlroy, still complain- ing of chest pain but not referring to his recent experience.When he saw JRN he had the grace to look a little embarrassed.The ECG machine in the Adelaide Hospital evidently caused the patient no further upset-and the tracing showed no abnormality.Nevertheless, he spent a comfortable night in hospital and subsequently took his own discharge.There is no doubt in our minds that this man was McIlroy....
Histopathology of the Host Response to Lewis Lung Carcinoma: Modulation by Pyran&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: M J Snodgrass, P S Morahan, A M Kaplan
Journal: JNCI Journal of the National Cancer Institute (1975)

The growth and metastasis of sc transplanted Lewis lung carcinoma were inhibited in C57BL/6J mice by treatment with pyran copolymer. The mean volume of the tumors of pyran-treated animals was 15% that of the saline-treated controls at day 33 post transplantation. Thereafter, the carcinomas gradually increased in volume. Pulmonary metastasis was first observed histologically at day 28 after pyran treatment, compared to day 15 after saline administration. All saline-treated animals died by day 48, whereas 70% of those given pyran remained alive. Tumor necrosis was much more extensive in the lesions of pyran-treated mice. Although neutrophils and monocytes, but few lymphocytes, infiltrated the subcutaneous connective tissue above the neoplasms of animals receiving saline, few leukocytes were present in other connective tissue sites around the tumor. In contrast, treatment with pyran was characterized by a shift at an early interval from a predominance of neutrophils to a predominance of histiocytes and some lymphocytes in the connective tissue above and around the subcutaneous tumor. These cells were often closely associated with degenerate-appearing tumor cells. Additionally, activated macrophages removed from the peritoneal cavity of pyran-treated, tumor-bearing mice exhibited nonspecific cytotoxicity for tumor cells in vitro.
Tissue Invasion by Unnamed Marine Vibrios
Authors: C. Raymond Fernandez
Journal: JAMA (1975)

Vibrio parahaemolyticus is an extremely common organism of major importance as a cause of gastroenteritis, but not common as a cause of tissue infection. Of three patients who had serious localized tissue infections, one died because of an unnamed marine Vibrio infection. Vibrios are easily isolated, although their final speciation is quite difficult in view of their unsettled taxonomic position. It is hoped that agreement can be reached as to bacteriologic genealogy; perhaps then the specific pathogenic manifestations will be clarified. The clinician should consider the possibility of this pathogen in any patient with a wound related to saltwater or seafood.
Absence of Adverse Effects in Cynomolgus Macaques Treated with CNTO 95, a Fully Human Anti-αv Integrin Monoclonal Antibody, Despite Widespread Tissue Binding
Authors: Pauline L. Martin, Qun Jiao, Joel Cornacoff, William Hall, Bradley Saville, Jeffrey A. Nemeth, Allen Schantz, Marielena Mata, Haishan Jang, Adedigbo A. Fasanmade, Lisa Anderson, Martin A. Graham, Hugh M. Davis, George Treacy
Journal: Clinical Cancer Research (2005)

Abstract Purpose: CNTO 95 is a fully human anti-αv integrin monoclonal antibody that inhibits macaque and rodent angiogenesis and inhibits human tumor growth in rodents. The purpose of these studies was to evaluate the preclinical safety of long-term administration of CNTO 95 in cynomolgus macaques. Experimental Design: The in vitro binding profiles of CNTO 95 to human and macaque tissues and the in vivo binding to macaque tissues was evaluated by immunohistochemistry. The preclinical safety of CNTO 95 (10 and 50 mg/kg, i.v.) was evaluated in macaques treated once per week for up to 6 months. Safety was evaluated by clinical observations, ophthalmic and physical examinations (including heart rate, blood pressure, and electrocardiogram), clinical pathology (including coagulation parameters), and comprehensive anatomic pathology. The effect of CNTO 95 (50 mg/kg, i.v.) on incisional wound healing was evaluated in macaques. Results: The tissue binding studies showed that CNTO 95 bound with mild to moderate intensity to macaque and human endothelial cells, epithelial cells, and vascular smooth muscle cells in most normal tissues examined. CNTO 95 showed strong to intense staining to the positive control tissue, human placenta. Despite the widespread binding to normal tissues, treatment of cynomolgus macaques with CNTO 95 produced no signs of toxicity and no histopathologic changes in any of the tissues examined (including ovaries and bone growth plates). CNTO 95 did not impair wound healing. Conclusion: These studies show that CNTO 95 is safe and, unlike some other angiogenesis inhibitors, does not seem to inhibit normal physiologic angiogenesis.
Bird flu: Pandemic flu preparation: an unheeded lesson from SARS
Authors: Meng-Kin Lim
Journal: BMJ (2006)

Activation of the Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup>-cotransporter (NKCC2) and the Na<sup>+</sup>-Cl<sup>−</sup>-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor–specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.
Do Patients With Schizophrenia Wish to Be Involved in Decisions About Their Medical Treatment?
Authors: Johannes Hamann, Rudolf Cohen, Stefan Leucht, Raymonde Busch, Werner Kissling
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Little is known about the desire of patients with schizophrenia to be involved in medical decisions affecting their treatment. METHOD: The authors administered the Autonomy Preference Index to 122 inpatients with schizophrenia. In addition, the patients filled out the Drug Attitude Inventory. Sociodemographic data and Positive and Negative Syndrome Scale ratings were available for all patients. RESULTS: The patients expressed a desire for shared decision making that was slightly greater than that of primary care patients. Negative attitudes toward medical treatment and younger age were associated with a higher desire for participation. CONCLUSIONS: It is important to meet the participation needs of patients who are dissatisfied with their psychiatric treatment.
Severe impairment of coronary reserve during rejection in patients with orthotopic heart transplant.
Authors: A Nitenberg, O Tavolaro, D Loisance, J M Foult, N Benhaiem, J P Cachera
Journal: Circulation (1989)

The present study analyzed coronary sinus blood flow alterations after dipyridamole induced coronary vasodilation in seven patients whose endomyocardial biopsies evidenced no sign of rejection (group 1) and in five patients with histologic signs of rejection (group 2) after orthotopic heart transplantation. All patients were treated with cyclosporine and prednisone and some with azathioprine and had normal coronary arteriograms. Coronary sinus blood flow and coronary resistance were measured before and after intravenous dipyridamole (0.18 mg/kg/min over 4 minutes). Basal values were similar in groups 1 and 2 for coronary sinus blood flow (166 +/- 34 compared with 181 +/- 39 ml/min, respectively), coronary resistance (0.62 +/- 10 compared with 0.52 +/- 13 mm Hg/ml/min, respectively), coronary sinus blood oxygen content (5.7 +/- 1.6 compared with 4.5 +/- 0.9 ml/100 ml, respectively) and arterial-coronary sinus blood oxygen difference (10.6 +/- 1.3 compared with 10.3 +/- 1.8 ml/100 ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
New Drugs for the Treatment of Diabetes
Authors: Silvio E. Inzucchi, Darren K. McGuire
Journal: Circulation (2008)

This is the second of a 2-part series focusing on newer therapies for type 2 diabetes and their cardiovascular implications. In the first segment, we reviewed the thiazolidinediones, highlighting emerging data concerning their cardiovascular effects, both positive and negative. Here, we present a corresponding discussion of the newest antihyperglycemic category, modulators of the incretin system, which include the glucagon-like peptide-1 mimetics and the dipeptidyl peptidase-4 inhibitors. In addition, we briefly survey several novel drug classes in development, provide summary recommendations for glucose-lowering regimens in specific patient types, underscore the importance of nonglucose cardiovascular risk reduction strategies, and comment on present and future considerations for the regulatory review of diabetes drugs.