tbuckley/cabot-search huggingface dataset:
Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent. Partial inhibition of the reaction with antiserum against tumor necrosis factor-alpha.
Authors: B K Wershil, Z S Wang, J R Gordon, S J Galli
Journal: Journal of Clinical Investigation (1991)

Much of the clinically important pathology associated with IgE-dependent disorders is thought to reflect the actions of the blood-borne leukocytes recruited during these responses. To evaluate the extent to which mast cells are responsible for the leukocyte infiltration associated with IgE-dependent cutaneous reactions, we attempted to elicit these responses in normal mice, genetically mast cell-deficient W/Wv mice, and in W/Wv mice selectively repaired of their mast cell deficiency by the intradermal injection of cultured mast cells derived from the congenic normal (+/+) mice. We found that the tissue swelling associated with IgE-dependent passive cutaneous anaphylaxis reactions developed rapidly and diminished markedly from 2 to 4 h after antigen challenge, but remained detectable for at least 24 h after elicitation of the responses. Infiltration of leukocytes (predominantly neutrophils) also occurred at these sites, but reached maximal levels 6-12 h after antigen challenge, persisted at high levels for 24 h, and largely waned by 48 h. Virtually all of the tissue swelling and leukocyte infiltration associated with IgE-dependent cutaneous reactions was mast cell dependent. Intradermal injection of 40 U of recombinant murine TNF-alpha (rmTNF-alpha) elicited neutrophil infiltration similar in magnitude and kinetics to that observed after IgE-dependent mast cell degranulation. A rabbit anti-rmTNF-alpha (R anti-rmTNF-alpha) antiserum, which was able to inhibit 84% of the neutrophil infiltration observed after i.d. injection of rmTNF-alpha, inhibited IgE-, and mast cell-dependent leukocyte infiltration by 47 +/- 7% in three separate experiments. These findings indicate that TNF-alpha contributes to mast cell-dependent recruitment of leukocytes during IgE-dependent cutaneous late phase reactions, but suggest that other mast cell-associated mediators probably also contribute to this response.
Inhibitory Effects of TA-993, a New 1,5-Benzothiazepine Derivative, on Platelet Aggregation
Authors: Akio Odawara, Kohei Kikkawa, Makoto Katoh, Hiromi Toryu, Tamotu Shimazaki, Yasuhiko Sasaki
Journal: Circulation Research (1996)

Abstract TA-993, an l - cis 4′,8-dimethyl derivative of the Ca 2+ antagonist diltiazem, and some of its metabolites inhibited platelet aggregation induced by collagen, ADP, epinephrine, platelet activating factor, arachidonic acid, and U-46619 in human platelets in vitro. Among the metabolites, MB3 was the most potent (IC 50 , &lt;1 μmol/L; several hundred times more potent than the parent compound). The d isomer of MB3 was &gt;100 times less potent than the l isomer. Unlike acetylsalicylic acid (ASA), TA-993 inhibited both primary and secondary phases of ADP-induced platelet aggregation and also exhibited a disaggregating effect on human platelet aggregates. The inhibitory effect of TA-993 was enhanced when used in combination with ASA. In ex vivo studies involving rats, TA-993 (≈0.3 to 100 mg/kg PO) dose-dependently inhibited collagen-induced platelet aggregation (ED 50 , 3 mg/kg PO). In the whole-blood platelet aggregation system in rats, orally administered TA-993 was also inhibitory in single (3 to 30 mg/kg) or repeated daily (10 mg/kg per day for 10 days) dosage. Orally administered TA-993 dose-dependently inhibited ADP-induced platelet aggregation ex vivo in dogs (0.3 to 10 mg/kg), significantly protected mice against collagen+epinephrine–induced thromboembolic death (10 mg/kg), and inhibited thrombus formation in an arteriovenous shunt in rats (30 mg/kg). The Ca 2+ -antagonistic action of TA-993 was very weak in depolarized canine basilar arteries: the potency was ≈1/10 that of diltiazem ( d - cis ) and d -TA-993. These results suggest that antiplatelet action is more characteristic of the l - cis than the d - cis 1,5-benzothiazepine structure and that TA-993 may become a clinically useful antiplatelet agent of this structure series.
Activation of the Gi Heterotrimeric G Protein by ANCA IgG F(ab′)2 Fragments Is Necessary but not Sufficient to Stimulate the Recruitment of Those Downstream Mediators Used by Intact ANCA IgG
Authors: Julie M Williams, Anne Ben-Smith, Peter Hewins, Stephen K Dove, Philip Hughes, Robert McEwan, Michael J O Wakelam, Caroline O S Savage
Journal: Journal of the American Society of Nephrology (2003)

Anti-neutrophil cytoplasm autoantibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. Intact ANCA IgG activate superoxide generation in cytokine-primed neutrophils after binding their antigens and co-engaging Fcγ receptors (FcγR). The contribution of antigen binding via ANCA F(ab′)2 fragments to signaling has been unclear. This study shows that both ANCA IgG and F(ab′)2 fragments of ANCA IgG induce significant GTPase activity, which could be blocked with pertussis toxin and anti-Gi protein antibodies. Pertussis toxin inhibited ANCA IgG-induced superoxide generation but was without effect on superoxide production after conventional FcγR ligation. ANCA F(ab′)2 fragments did not induce superoxide generation. ANCA IgG activated PI 3-kinase–generating PIP3, activated protein kinase B (PKB), and p21ras; activation of each mediator was inhibited with pertussis toxin, but PI3K and PKB were not activated by ANCA IgG F(ab′)2 fragments. Intact ANCA IgG induced tyrosine phosphorylation, whereas F(ab′)2 fragments did not, and ANCA IgG-mediated superoxide generation was inhibited with genistein. Both genistein and pertussis toxin together completely abrogated the ANCA-induced oxidative burst. Genistein also inhibited ANCA IgG-induced PIP3 generation and p21ras activation. These data implicate a novel ANCA IgG stimulated signaling pathway that involves both F(ab′)2-mediated antigen binding and Fc-mediated FcγR ligation in cooperative interactions between Gi proteins and tyrosine kinases that facilitates activation of downstream mediators. E-mail: C.O.S.Savage@bham.ac.uk.
Glucagon-like peptide-1 is a physiological incretin in rat.
Authors: Z Wang, R M Wang, A A Owji, D M Smith, M A Ghatei, S R Bloom
Journal: Journal of Clinical Investigation (1995)

Glucagon-like peptide-1 7-36 amide (GLP-1) has been postulated to be the primary hormonal mediator of the entero-insular axis but evidence has been indirect. The discovery of exendin (9-39), a GLP-1 receptor antagonist, allowed this to be further investigated. The IC50 for GLP-1 receptor binding, using RIN 5AH beta-cell membranes, was found to be 0.36 nmol/l for GLP-1 and 3.44 nmol/l for exendin (9-39). There was no competition by exendin (9-39) at binding sites for glucagon or related peptides. In the anaesthetized fasted rat, insulin release after four doses of GLP-1 (0.1, 0.2, 0.3, and 0.4 nmol/kg) was tested by a 2-min intravenous infusion. Exendin (9-39) (1.5, 3.0, and 4.5 nmol/kg) was administered with GLP-1 0.3 nmol/kg, or saline, and only the highest dose fully inhibited insulin release. Exendin (9-39) at 4.5 nmol/kg had no effect on glucose, arginine, vasoactive intestinal peptide or glucose-dependent insulinotropic peptide stimulated insulin secretion. Postprandial insulin release was studied in conditioned conscious rats after a standard meal. Exendin (9-39) (0.5 nmol/kg) considerably reduced postprandial insulin concentrations, for example by 48% at 15 min (431 +/- 21 pmol/l saline, 224 +/- 32 pmol/l exendin, P < 0.001). Thus, GLP-1 appears to play a major role in the entero-insular axis.
Antibodies recognising sulfated carbohydrates are prevalent in systemic sclerosis and associated with pulmonary vascular disease
Authors: T. Grader-Beck, F. Boin, S. von Gunten, D. Smith, A. Rosen, B. S. Bochner
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Glycosylation represents an important modification that regulates biological processes in tissues relevant for disease pathogenesis in systemic sclerosis (SSc), including the endothelium and extracellular matrix. Whether patients with SSc develop antibodies to carbohydrates is not known. <h3>Objectives</h3> To determine the prevalence and clinical phenotype associated with serum IgG antibodies recognising distinct glycans in patients with SSc. <h3>Methods</h3> Pooled serum samples from patients with SSc and controls were screened for the presence of specific anticarbohydrate antibodies using a novel array containing over 300 glycans. Antibody titres to 4-sulfated N-acetyl-lactosamine (4S-LacNAc, (4OSO3)Galβ1-4GlcNAc) were determined in 181 individual serum samples from patients with SSc by ELISA and associated with disease phenotype. <h3>Results</h3> 4S-LacNAc was identified as a target in pooled SSc serum. Anti-4S-LAcNAc antibodies were detected in 27/181 patients with SSc (14.9%) compared with 1/40 healthy controls (2.5%). Sulfation at position C4 of galactose (4S-LacNAc) was found to be critical for immunogenicity. Anti-4S-LacNAc antibody-positive patients with SSc had a higher prevalence of pulmonary hypertension by echocardiography than anti-4S-LacNAc-negative patients (15/27 (55.7%) vs 49/154 (31.8%), p=0.02) with an OR of 2.6 (95% CI 1.1 to 6.3). Anti-4S-LacNAc-positive patients accounted for 23.4% of all patients with pulmonary hypertension. <h3>Conclusion</h3> Serum from patients with SSc contains IgG antibodies targeting distinct sulfated carbohydrates. The presence of anti-4S-LacNAc antibodies is associated with a high prevalence of pulmonary hypertension. These results suggest that specific post-translational carbohydrate modifications may act as important immunogens in SSc and may contribute to disease pathogenesis.
MRI does not add value over and above patient history and clinical examination in predicting time to return to sport after acute hamstring injuries: a prospective cohort of 180 male athletes
Authors: Arnlaug Wangensteen, Emad Almusa, Sirine Boukarroum, Abdulaziz Farooq, Bruce Hamilton, Rodney Whiteley, Roald Bahr, Johannes L Tol
Journal: British Journal of Sports Medicine (2015)

MRI is frequently used in addition to clinical evaluation for predicting time to return to sport (RTS) after acute hamstring injury. However, the additional value of MRI to patient history taking and clinical examination remains unknown and is debated.To prospectively investigate the predictive value of patient history and clinical examination at baseline alone and the additional predictive value of MRI findings for time to RTS using multivariate analysis while controlling for treatment confounders.Male athletes (N=180) with acute onset posterior thigh pain underwent standardised patient history, clinical and MRI examinations within 5 days, and time to RTS was registered. A general linear model was constructed to assess the associations between RTS and the potential baseline predictors. A manual backward stepwise technique was used to keep treatment variables fixed.In the first multiple regression model including only patient history and clinical examination, maximum pain score (visual analogue scale, VAS), forced to stop within 5 min, length of hamstring tenderness and painful resisted knee flexion (90°), showed independent associations with RTS and the final model explained 29% of the total variance in time to RTS. By adding MRI variables in the second multiple regression model, maximum pain score (VAS), forced to stop within 5 min, length of hamstring tenderness and overall radiological grading, showed independent associations and the adjusted R(2) increased from 0.290 to 0.318. Thus, additional MRI explained 2.8% of the variance in RTS.There was a wide variation in time to RTS and the additional predictive value of MRI was negligible compared with baseline patient history taking and clinical examinations alone. Thus, clinicians cannot provide an accurate time to RTS just after an acute hamstring injury. This study provides no rationale for routine MRI after acute hamstring injury.ClinicalTrials.gov Identifier: NCT01812564.
Effects of extracellular calcium ions, verapamil, and lanthanum on active and passive properties of canine cardiac purkinje fibers.
Authors: M L Pressler, V Elharrar, J C Bailey
Journal: Circulation Research (1982)

The effects of alteration of extracellular calcium ion concentration ([Ca++]o) were studied in isolated false tendons using microelectrode techniques. Several determinants of cellular excitability and conduction velocity were affected by extracellular calcium. Increasing [Ca++]o from 2 to 8 mM resulted in: (1) a progressive decrease in interelectrode conduction velocity (2) a 7-mV shift of the maximum upstroke velocity-membrane potential relation toward less negative potential, (3) an increase in rheobasic current, (4) a 14-mV shift of the voltage threshold for all-or-none depolarization to less negative potentials, (5) a 52% increase in internal longitudinal resistance per unit length, and (6) a 27% decrease in the capacitance filled by the foot of the action potential from 4.90 to 3.56 microF/cm2. Blockade of the slow inward current by Mn++ or verapamil did not alter the [Ca++]o-induced effects on the maximum upstroke velocity-membrane potential relation. Cable properties were determined during alteration of [Ca++]o in the presence of verapamil (3 X 10(-6) and 1 X 10(-5) M) or in the presence of La+++ (0.2 mM). Verapamil increased membrane resistance X unit length but did not affect internal longitudinal resistance per unit length. La+++ had no effects on either membrane resistance X unit length or internal longitudinal resistance per unit length. Verapamil did not block the increase in ri induced by elevation of [Ca++]o. However, no change in ri occurred during an increase of [Ca++]o when La+++ was present. The results suggest that [Ca++]o-induced changes in internal longitudinal resistance may occur by the influx of calcium ions through the Na+/Ca++ exchange mechanism.
Recovery of attenuated baroreflex sensitivity in conscious dogs after reversal of pacing induced heart failure
Authors: E. A Grima, G. W Moe, R. J Howard, P. W Armstrong
Journal: Cardiovascular Research (1994)

Objective: Rapid ventricular pacing reliably induces severe congestive heart failure in dogs, with an associated attenuation of baroreflex sensitivity. Unique to this model is the capacity for rapid recovery of haemodynamics and plasma noradrenaline following the cessation of pacing; however, whether baroreflex sensitivity will similarly recover is unknown. The aims of this study were (1) to assess baroreflex control of heart rate in response to acute hypertensive and hypotensive stimuli during the development of and recovery from severe heart failure, and (2) to correlate baroreflex sensitivity with haemodynamic and echocardiographic indices and with noradrenaline concentrations. Methods: Serial assessments were performed on six dogs paced to severe heart failure and then allow to recover for four weeks. R-R interval and systolic blood pressure were monitored during administrations of phenylephrine and nitroprusside and the slope (ms·mm Hg−1) of the resultant R-R interval- systolic blood pressure relationship was used to define baroreflex sensitivity. Results: Control phenylephrine and nitroprusside derived slopes were 27.05(SD 7.88) and 17.1(11.03) ms·mm Hg−1 respectively. After one week of pacing the phenylephrine derived slope was unchanged while the nitroprusside slope tended to be attenuated. In severe heart failure, both slopes were severely attenuated, at 1.88(6.45) ms·mm Hg−1 (phenylephrine) and 4.21(3.28) ms·mm Hg−1 (nitroprusside) (both p<0.05). Intrinsic heart rate, noradrenaline concentrations and cardiac filling pressures were raised at severe heart failure while cardiac output and systolic blood pressure were significantly reduced. Recovery of baroreflex control of heart rate was evident as early as 48 h following pacing cessation and was maintained after four weeks recovery. Haemodynamics, cardiac output, and noradrenaline also returned to control while cardiac dilatation persisted. Nitroprusside and phenylephrine derived slopes were inversely correlated with intrinsic heart rate and pulmonary arterial/capillary wedge pressures respectively. Conclusions: Despite marked attenuation of baroreflex control of heart rate at severe heart failure, rapid recovery was seen in response to both hypotensive and hypertensive stimuli. The speed with which recovery occurs suggests that attenuation of baroreflex sensitivity at severe heart failure is likely to be mediated by functional alterations rather than morphological damage. Cardiovascular Research 1994;28:384-390
Studies of <i>TMPRSS2-ERG</i> Gene Fusions in Diagnostic Trans-Rectal Prostate Biopsies
Authors: Gerhardt Attard, Johann S. de Bono, Jeremy Clark, Colin S. Cooper
Journal: Clinical Cancer Research (2010)

To the Editor: The recent article by Mosquera et al. reports TMPRSS2-ERG fusions in 46% of 100 trans-rectal biopsies of the prostate (TRBP) from prostate-specific antigen screened men in the United States (1) and compares this to the lower prevalence of ERG translocations in cancer detected incidentally on trans-urethral resection of the prostate (TURP). We agree with the authors that the lower prevalence of ERG rearrangements observed in our and other studies of specimens obtained from watchful-waiting men (2) is unlikely to be due to genetic differences between U.S. and European patients. The authors have attributed this observation to the overrepresentation of men with clinically insignificant, indolent disease in the watchful-waiting group, which is based on the assumption that an isolated TMPRSS2-ERG fusion is associated with worse outcome. This remains controversial as a number of studies now suggest that the combination of TMPRSS2-ERG fusion and copy number gain or additional genetic aberrations such as PTEN loss is required for worse outcome (3). More studies, preferably multicenter, evaluating these prognostic markers in well-defined patient cohorts are urgently required. In our recent study of TRBP specimens from 48 patients who all ultimately progressed and developed fatal prostate cancer, we reported ERG rearrangements in 20 patients (41%; ref. 4), which is a very similar prevalence to Mosquera et al.'s cohort of patients (1) who have a relatively low chance of developing fatal disease: If the presence of an ERG rearrangement was associated with fatal disease, one would have expected our cohort of men to have been enriched for ERG-rearranged cancers when compared with Mosquera et al.'s study. Other explanations for the lower prevalence of ERG rearrangements in the watchful-waiting TURP cancers should therefore be considered. One explanation could be that cancers arising in the para-urethral region have a lower prevalence of ERG rearrangements, as has been described by Guo et al. (5), and therefore ERG-rearranged cancers arising peripherally are less likely to be detected incidentally by TURP. Also interestingly, we and Mosquera et al. report significantly less heterogeneity in TRBP (3 of 48 and 2 of 100 patients, respectively; refs. 1, 4) than would have been predicted from ETS gene studies of prostatectomies (3): It is therefore possible that the largest tumor focus (arising in the peripheral zone) that is most likely to account for the majority or all of TRBP cores has a uniform ERG status and is genetically distinct from cancers arising elsewhere. These observations have important implications for the development of ETS gene translocations as biomarkers for prostate cancer.No potential conflicts of interest were disclosed.
Heart Disease May Be a Risk Factor for Pulmonary Embolism Without Peripheral Deep Venous Thrombosis
Authors: Henrik T. Sørensen, Erzsebet Horvath-Puho, Timothy L. Lash, Christian F. Christiansen, Raffaele Pesavento, Lars Pedersen, John A. Baron, Paolo Prandoni
Journal: Circulation (2011)

Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain.We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45,282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59,790 had deep venous thrombosis alone; 541,561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6-47.8] and 32.4 [95% CI, 29.8-35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0-24.2] and 22.1 [95% CI, 18.7-26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6-10.7] and 12.7 [95% CI, 11.6-13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3-16.1), whereas the odds ratio was 74.6 (95% CI, 28.4-195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern.Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.
Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells.
Authors: L J Muglia, N A Jenkins, D J Gilbert, N G Copeland, J A Majzoub
Journal: Journal of Clinical Investigation (1994)

Corticotropin-releasing hormone (CRH), one of the primary regulators of the hypothalamic-pituitary-adrenal (HPA) axis, exhibits abnormal regulation in pathologic states such as depression and anorexia nervosa. Analysis of the role of CRH in regulation of the HPA axis would be facilitated by the creation of animal models in which CRH gene structure and function could be manipulated. We have determined the DNA sequence of the mouse CRH gene. Using a highly sensitive reverse transcription-polymerase chain reaction method, we have found expression of CRH mRNA in adrenal, ovary, testis, gut, heart, anterior pituitary, lung, and spleen, in addition to cerebral cortex and hypothalamus. Within the spleen, CRH mRNA is localized specifically to T-lymphocytes. We mapped the chromosomal location of mouse CRH via interspecific mouse backcrosses to chromosome 3, which is not the site of any naturally occurring mutations consistent with CRH deficiency. Because of this, we inactivated a CRH allele in mouse embryonic stem (ES) cells by homologous recombination with a mutant mouse CRH gene lacking the entire coding region of preproCRH. Mice chimeric for each of two ES clones with an inactivated CRH allele are being used to generate animals with complete CRH deficiency.