tbuckley/cabot-search huggingface dataset:
Vitamin D Levels and Asymptomatic Coronary Artery Disease in Type 2 Diabetic Patients With Elevated Urinary Albumin Excretion Rate
Authors: Christel Joergensen, Henrik Reinhard, Anne Schmedes, Peter R. Hansen, Niels Wiinberg, Claus L. Petersen, Kaj Winther, Hans-Henrik Parving, Peter K. Jacobsen, Peter Rossing
Journal: Diabetes Care (2011)

OBJECTIVE Coronary artery disease (CAD) is the major cause of morbidity and mortality in type 2 diabetic patients. Severe vitamin D deficiency has been shown to predict cardiovascular mortality in type 2 diabetic patients. RESEARCH DESIGN AND METHODS We investigated the association among severe vitamin D deficiency, coronary calcium score (CCS), and asymptomatic CAD in type 2 diabetic patients with elevated urinary albumin excretion rate (UAER) &amp;gt;30 mg/24 h. This was a cross-sectional study including 200 type 2 diabetic patients without a history of CAD. Severe vitamin D deficiency was defined as plasma 25-hydroxyvitamin D (p-25[OH]D3) &amp;lt;12.5 nmol/L. Patients with plasma N-terminal pro-brain natriuretic peptide &amp;gt;45.2 ng/L or CCS ≥400 were stratified as being high risk for CAD (n= 133). High-risk patients were examined by myocardial perfusion imaging (MPI; n = 109), computed tomography angiography (n = 20), or coronary angiography (CAG; n = 86). Patients’ p-25(OH)D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry. RESULTS The median (range) vitamin D level was 36.9 (3.8–118.6) nmol/L. The prevalence of severe vitamin D deficiency was 9.5% (19/200). MPI or CAG demonstrated significant CAD in 70 patients (35%). The prevalence of CCS ≥400 was 34% (68/200). Severe vitamin D deficiency was associated with CCS ≥400 (odds ratio [OR] 4.3, 95% CI [1.5–12.1], P = 0.005). This association persisted after adjusting for risk factors (4.6, 1.5–13.9, P = 0.007). Furthermore, severe vitamin D deficiency was associated with asymptomatic CAD (adjusted OR 2.9, 1.02–7.66, P = 0.047). CONCLUSIONS In high-risk type 2 diabetic patients with elevated UAER, low levels of vitamin D are associated with asymptomatic CAD.
MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF
Authors: Masahisa Jinushi, Yukoh Nakazaki, Michael Dougan, Daniel R. Carrasco, Martin Mihm, Glenn Dranoff
Journal: Journal of Clinical Investigation (2007)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF-deficient mice develop inflammatory disease. Here we show that GM-CSF is required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8-mediated uptake of apoptotic cells is a key determinant of GM-CSF-triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF-deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-gamma promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF-secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF-stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4(+) T cell subsets in cancer and autoimmunity.
Filamentous Bacteriophage Promote Biofilm Assembly and Function
Authors: Patrick R. Secor, Johanna M. Sweere, Lia A. Michaels, Andrey V. Malkovskiy, Daniel Lazzareschi, Ethan Katznelson, Jayakumar Rajadas, Michael E. Birnbaum, Allison Arrigoni, Kathleen R. Braun, Stephen P. Evanko, David A. Stevens, Werner Kaminsky, Pradeep K. Singh, William C. Parks, Paul L. Bollyky
Journal: Cell Host & Microbe (2015)

Highlights•Filamentous Pf bacteriophage are produced by Pseudomonas aeruginosa•Pf phage interact with host and microbial polymers to assemble higher order structures•Pf phage increase the viscosity of polymers in cystic fibrosis airway secretions•The Pf-induced liquid crystal biofilm matrix boosts tolerance to desiccation and antibioticsSummaryBiofilms—communities of bacteria encased in a polymer-rich matrix—confer bacteria with the ability to persist in pathologic host contexts, such as the cystic fibrosis (CF) airways. How bacteria assemble polymers into biofilms is largely unknown. We find that the extracellular matrix produced by Pseudomonas aeruginosa self-assembles into a liquid crystal through entropic interactions between polymers and filamentous Pf bacteriophages, which are long, negatively charged filaments. This liquid crystalline structure enhances biofilm function by increasing adhesion and tolerance to desiccation and antibiotics. Pf bacteriophages are prevalent among P. aeruginosa clinical isolates and were detected in CF sputum. The addition of Pf bacteriophage to sputum polymers or serum was sufficient to drive their rapid assembly into viscous liquid crystals. Fd, a related bacteriophage of Escherichia coli, has similar biofilm-building capabilities. Targeting filamentous bacteriophage or the liquid crystalline organization of the biofilm matrix may represent antibacterial strategies.Graphical abstract
Electrophysiological effects of some antidepressant drugs on canine cardiac Purkinje fibres
Authors: A. BRIL, L. ROCHETTE, J. P. BERTRAND, P. GAUTIER
Journal: Cardiovascular Research (1987)

The electrophysiological effects of several antidepressant drugs, imipramine, metapramine, mianserin, nomifensine, and amineptine, were studied in canine cardiac Purkinje fibres at concentrations between 10−6 mol·litre−1 and 10−4 mol·litre−1. Metapramine (10−5 mol·litre−1) decreased the action potential amplitude, the action potential duration, and Vmax. In addition, imipramine or metapramine induced a pronounced increase of conduction time and conduction block at 10−4 mol·litre−1, whereas with mianserin and nomifensine a 10−4 mol·litre−1 concentration was necessary to induce a decrease of Vmax and conduction velocity. With the exception of conduction time and action potential duration, amineptine was not able significantly to change the electro- physiological indices of canine Purkinje fibres. The decrease of Vmax observed with imipramine, metapramine, and with high concentrations of mianserin and nomifensine confirms that the antiarrhythmic action of these agents might be related principally to their class I antiarrhythmic effects. The fact that amineptine, which is not antiarrhythmic, does not decrease Vmax reinforces this suggestion.
Conformational Change in Transfer RNA Is an Early Indicator of Acute Cellular Damage
Authors: Eikan Mishima, Chisako Inoue, Daisuke Saigusa, Ryusuke Inoue, Koki Ito, Yusuke Suzuki, Daisuke Jinno, Yuri Tsukui, Yosuke Akamatsu, Masatake Araki, Kimi Araki, Ritsuko Shimizu, Haruka Shinke, Takehiro Suzuki, Yoichi Takeuchi, Hisato Shima, Yasutoshi Akiyama, Takafumi Toyohara, Chitose Suzuki, Yoshikatu Saiki, Teiji Tominaga, Shigehito Miyagi, Naoki Kawagisihi, Tomoyoshi Soga, Takayoshi Ohkubo, Kenichi Yamamura, Yutaka Imai, Satohiro Masuda, Venkata Sabbisetti, Takaharu Ichimura, David B. Mount, Joseph V. Bonventre, Sadayoshi Ito, Yoshihisa Tomioka, Kunihiko Itoh, Takaaki Abe
Journal: Journal of the American Society of Nephrology (2014)

Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In various models of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.
DEFECTS IN HEMATOPOIETIC DIFFERENTIATION IN NZB AND NZC MICE
Authors: Noel L. Warner, Malcolm A. S. Moore
Journal: The Journal of Experimental Medicine (1971)

Hematopoietic stem cell activity in inbred NZB and NZC mice has been determined by transplantation and endogenous spleen colony assays. Whereas NZB mice show normal colony-forming unit (CFU) activity in the transplantation assay, they show markedly elevated endogenous CFU. NZC mice also show this markedly elevated endogenous CFU activity, but in the transplantation assay show only about 5-10% of normal CFU counts. When NZC stem cells are tested for CFU activity in irradiated recipients of the H-2(d) type, almost normal colony numbers occur. NZB stem cells however also cannot form colonies in NZC mice. These results suggest that NZC mice have a defect in the micro-environment of the spleen which renders them incapable of allowing transplanted CFU to form colonies. Genetic analysis of both the NZC defect as a CFU recipient, and the elevated endogenous count in NZB and NZC, shows that both are controlled by single recessive genes which are not linked to either coat color, agouti, H-2 or Ig loci. Of even more relevance is the finding that these hematopoietic abnormalities are not linked to the genes involved in controlling autoantibody formation to red cells in the NZB mice. These mice therefore appear to show two distinct hematopoietic abnormalities, the analysis of which may be of considerable value in understanding the detailed events of hematopoietic stem cell differentiation.
Allopurinol treatment and its effect on renal function in gout: a controlled study.
Authors: T Gibson, V Rodgers, C Potter, H A Simmonds
Journal: Annals of the Rheumatic Diseases (1982)

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.
Interleukin-1β (IL-1β) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis
Authors: Frederic A Carvalho, Ilke Nalbantoglu, Sophie Ortega-Fernandez, Jesse D Aitken, Yueju Su, Omry Koren, William A Walters, Rob Knight, Ruth E Ley, Matam Vijay-Kumar, Andrew T Gewirtz
Journal: Gut (2011)

<h3>Background</h3> The extent to which numerous strains of genetically engineered mice, including mice lacking Toll-like receptor 5 (T5KO), display colitis is environment dependent. Gut microbiota underlie much of the variation in phenotype. Accordingly, embryonic rederivation of T5KO mice ameliorated their spontaneous colitis despite only partially correcting elevated proinflammatory gene expression. It was postulated that endogenous anti-inflammatory pathways mediated the absence of overt inflammation in these mice when their gut microbiota were reset. Consequently, it was hypothesised that neutralisation of the anti-inflammatory cytokine interleukin 10 (IL-10) might induce uniform colitis in T5KO mice, and thus provide a practical means to study mechanisms underlying their inflammation. <h3>Methods</h3> Two distinct strains of non-colitic T5KO mice, as well as mice lacking MyD88, Toll-like receptor 4 (TLR4), IL-1 receptor (IL-1R) and various double knockouts (DKOs) were treated weekly for 4 weeks with 1 mg/mouse of IL-10 receptor neutralising antibody (IL-10R mAb) and colitis assayed 1 week later. The composition of the caecal microbiota was determined by 454 pyrosequencing of 16S rRNA genes. <h3>Results</h3> Anti-IL-10R mAb treatment led to severe uniform intestinal inflammation in both strains of T5KO mice. Such neutralisation of IL-10 signalling did not cause colitis in wild-type littermates nor mice lacking TLR4, MyD88 or IL-1R. The susceptibility of T5KO mice to this colitis model was not rescued by absence of TLR4 in that T4/T5 DKO mice displayed severe colitis in response to anti-IL-10R mAb treatment. IL-1β signalling was crucial for this colitis model in that IL-1R/T5 DKOs were completely protected from colitis in response to IL-10R mAb treatment. Lastly, it was observed that blockade of IL-10R function was associated with changes in the composition of gut microbiota, which were observed in mice that were susceptible and resistant to IL-10R mAb-induced colitis. <h3>Conclusion</h3> Regardless of whether they harbour a colitogenic microbiota, loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1β-dependent pathway.
Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans.
Authors: J A Wisneski, E W Gertz, R A Neese, M Mayr
Journal: Journal of Clinical Investigation (1987)

Free fatty acids are considered to be the major energy source for the myocardium.To investigate the metabolic fate of this substrate in humans, 24 subjects underwent coronary sinus and arterial catheterization. 13subjects were healthy volunteers and 11 subjects had symptoms of ischemic heart disease.I1-14CIoleate or 11-'4Cipalmitate bound to albumin was infused at a constant rate of 25 1Ci/h.Oxidation was determined by measuring the '4C02 production.The data demonstrated that a high percentage (84±17%) of the palmitate and oleate extracted by the myocardium underwent rapid oxidation.A highly significant correlation was present between the arterial level and the amount oxidized (r = 0.82, P < 0.001 for palmitate; r = 0.77, P < 0.001 for oleate).The isotope extraction ratio was greater than the chem- ical extraction ratio.This difference of 6±2 nmol/ml of blood in the young normal subjects was significantly less than the 12±4 nmol/ml observed in the ischemic heart disease patients (P < 0.001).
Effectiveness of Haemophilus influenzae Type b Conjugate Vaccine Introduction Into Routine Childhood Immunization in Kenya
Authors: Karen D. Cowgill, Moses Ndiritu, Joyce Nyiro, Mary P. E. Slack, Salome Chiphatsi, Amina Ismail, Tatu Kamau, Isaiah Mwangi, Mike English, Charles R. J. C. Newton, Daniel R. Feikin, J. Anthony G. Scott
Journal: JAMA (2006)

ContextHaemophilus influenzae type b (Hib) conjugate vaccine is not perceived as a public health priority in Africa because data on Hib disease burden and vaccine effectiveness are scarce. Hib immunization was introduced in Kenyan infants in 2001.ObjectiveTo define invasive Hib disease incidence and Hib vaccine program effectiveness in Kenya.Design, Setting, and PatientsCulture-based surveillance for invasive Hib disease at Kilifi District Hospital from 2000 through 2005 was linked to demographic surveillance of 38 000 children younger than 5 years in Kilifi District, Kenya. Human immunodeficiency virus (HIV) infection and Hib vaccination status were determined for children with Hib disease admitted 2002-2005.InterventionsIntroduction of conjugate Hib vaccine within the routine childhood immunization program at ages 6, 10, and 14 weeks beginning November 2001.Main Outcome MeasuresIncidence of culture-proven Hib invasive disease before and after vaccine introduction and vaccine program effectiveness.ResultsPrior to vaccine introduction, the median age of children with Hib was 8 months; case fatality was 23%. Among children younger than 5 years, the annual incidence of invasive Hib disease 1 year before and 1 and 3 years after vaccine introduction was 66, 47, and 7.6 per 100 000, respectively. For children younger than 2 years, incidence was 119, 82, and 16 per 100 000, respectively. In 2004-2005, vaccine effectiveness was 88% (95% confidence interval, 73%-96%) among children younger than 5 years and 87% (95% confidence interval, 66%-96%) among children younger than 2 years. Of 53 children with Hib admitted during 2002-2005, 29 (55%) were age-ineligible to have received vaccine, 12 (23%) had not been vaccinated despite being eligible, and 12 (23%) had received 2 or more doses of vaccine (2 were HIV positive).ConclusionsIn Kenya, introduction of Hib vaccine into the routine childhood immunization program reduced Hib disease incidence among children younger than 5 years to 12% of its baseline level. This impact was not observed until the third year after vaccine introduction.
Tumor Angiogenesis Promoted by <i>Ex vivo</i> Differentiated Endothelial Progenitor Cells Is Effectively Inhibited by an Angiogenesis Inhibitor, TK1-2
Authors: Ho-Kyun Oh, Jung-Min Ha, Eunju O, Byung Hun Lee, Suk Keun Lee, Byoung-Shik Shim, Yong-Kil Hong, Young Ae Joe
Journal: Cancer Research (2007)

Neovascularization plays a critical role in the growth and metastatic spread of tumors and involves recruitment of circulating endothelial progenitor cells (EPC) from bone marrow as well as sprouting of preexisting endothelial cells. In this study, we examined if EPCs could promote tumor angiogenesis and would be an effective cellular target for an angiogenesis inhibitor, the recombinant kringle domain of tissue-type plasminogen activator (TK1-2). When TK1-2 was applied in the ex vivo culture of EPCs isolated from human cord blood, TK1-2 inhibited adhesive differentiation of mononuclear EPCs into endothelial-like cells. In addition, it inhibited the migration of ex vivo cultivated EPCs and also inhibited their adhesion to fibronectin matrix or endothelial cell monolayer. When A549 cancer cells were coimplanted along with ex vivo cultivated EPCs s.c. in nude mice, the tumor growth was increased. However, the tumor growth and the vascular density of tumor tissues increased by coimplanted EPCs were decreased upon TK1-2 treatment. Accordingly, TK1-2 treatment reduced the remaining number of EPCs in tumor tissues and their incorporation into the host vascular channels. In addition, overall expression levels of vascular endothelial growth factor (VEGF) and von Willebrand factor in tumor tissues were decreased upon TK1-2 treatment. Interestingly, strong VEGF expression by implanted EPCs was decreased by TK1-2. Finally, we confirmed in vitro that TK1-2 inhibited VEGF secretion of EPCs. TK1-2 also inhibited endothelial cell proliferation and migration induced by the conditioned medium of EPCs. Therefore, we concluded that EPCs, as well as mature endothelial cells, could be an important target of TK1-2.
Inhalation of vasoactive intestinal peptide in pulmonary hypertension
Authors: H. H. Leuchte, C. Baezner, R. A. Baumgartner, D. Bevec, G. Bacher, C. Neurohr, J. Behr
Journal: European Respiratory Journal (2008)

Pulmonary hypertension (PH) leads to an increased right ventricular workload, cardiac failure and death. In idiopathic pulmonary arterial hypertension (PAH) the vasodilating vasoactive intestinal peptide (aviptadil) is deficient. The aim of the present study was to test the acute effects on haemodynamics and blood gases, and the safety, of a single dose of inhaled aviptadil in chronic PH. A total of 20 patients with PH (PAH in nine, PH in lung disease in eight and chronic thromboembolic PH in three) inhaled a single 100-µg dose of aviptadil during right-heart catheterisation. Haemodynamics and blood gases were measured. Aviptadil aerosol caused a small and temporary but significant selective pulmonary vasodilation, an improved stroke volume and mixed venous oxygen saturation. Overall, six patients experienced a pulmonary vascular resistance reduction of &gt;20%. In patients with significant lung disease, aviptadil tended to improve oxygenation. The pulmonary vasodilating effect of aviptadil aerosol was modest and short-lived, did not cause any side-effects and led to a reduced workload of the right ventricle without affecting systemic blood pressure. Aviptadil inhalation tended to improve oxygenation in patients with significant lung disease. Further studies are needed to evaluate the full therapeutic potential of aviptadil aerosol, including higher doses and chronic treatment.
Viral Carcinogenesis: Phenomena of Special Significance in the Search for a Viral Etiology in Human Cancers
Authors: Albert B. Sabin
Journal: Cancer Research (1968)

provides an excellent critical evaluation of our current knowl edge of some aspects of this problem. My purpose in this com munication is to synthesize that part of our knowledge of viral carcinogenesis that has a special bearing on the search for a viral etiology in human cancers, and to indicate what has been learned thus far and what is currently being done to determine whether any human malignancy may be caused by a virus. Despite many illuminating studies on the mechanism and phenomena of viral carcinogenesis in recent years, it is still not possible to say that any human malignancy is or is not caused by a virus. The establishment of the viral etiology of certain naturally occurring malignancies of lower animals, such as cer tain leukemias and sarcomas of chickens and mice and of mam mary carcinoma of mice, was achieved by the old, classical virologie technics of serial transmission with cell-free extracts in appropriate hosts of the same species. Since this approach, for a variety of reasons, cannot be used in the study of human malignancy, it is of special interest to examine the data, which have provided in vitro methods for identifying the causative viruses of the naturally occurring malignancies of lower animals and the phenomena associated with the malignancies that are produced experimentally by certain viruses which permit identi fication of the causative virus in the absence of infectious virus in the tumor.
Early T Lymphocyte Progenitors
Authors: Ken Shortman, Li Wu
Journal: Annual Review of Immunology (1996)

The earliest steps along the pathway leading to T cells in mice and humans are reviewed. These are the steps between the multipotent hemopoietic stem cell (HSC) and the fully committed precursors undergoing T cell receptor (TCR) gene rearrangement. At this level significant differences between adult and fetal lymphopoiesis have been demonstrated. The extent of lymphoid commitment of precursors within bone marrow is still unresolved, although HSCs clearly undergo developmental changes before migration to the thymus. Both multipotent and T-restricted precursors have now been isolated from fetal blood, suggesting both may seed the thymus. Within the thymus, several minute but discrete populations of T precursors precede the stage of TCR gene rearrangement. They include precursors that are not exclusively T-lineage committed, although they are distinct from HSCs. These precursors have a potential to form NK cells, B cells, dendritic cells, and sometimes other myeloid cells. Some factors that control early lymphoid development are discussed, including IL-7 and the Ikaros transcription factors. These will eventually help to clarify the process of T-lineage commitment.