tbuckley/cabot-search huggingface dataset:
Oxypurinol limits myocardial stunning but does not reduce infarct size after reperfusion.
Authors: D W Puett, M B Forman, C U Cates, B H Wilson, K R Hande, G C Friesinger, R Virmani
Journal: Circulation (1987)

To explore the role of oxygen free radicals produced by the xanthine oxidase pathway on infarct size and left ventricular function, the effect of oxypurinol, an active metabolite of allopurinol and a potent noncompetitive inhibitor of xanthine oxidase, was assessed in a 90 min, closed-chest, canine preparation of occlusion-reperfusion. Animals were randomized to receive 25 mg/kg iv oxypurinol (n = 13) or saline (n = 13) 60 min after occlusion. Regional myocardial blood flow was measured with radioactive microspheres and regional ventricular function with contrast ventriculography. Hemodynamic variables, regional myocardial blood flow, and size of the occluded bed were similar in the two groups. Oxypurinol failed to reduce infarct size 24 hr after reperfusion when expressed as a percentage of the area at risk (36.3 +/- 4.9% vs 36.0 +/- 5.6%; p = NS). Both groups exhibited comparative radial shortening at baseline and similar degrees of dyskinesia 1 hr into occlusion (-6.6 +/- 1.2% vs -4.9 +/- 1.0%). However, oxypurinol-treated animals demonstrated an improved regional ventricular function at 3 hr after reperfusion (0.7 +/- 2.6% vs -2.8 +/- 2.0%) and a significant improvement at 24 hr (5.4 +/- 2.5% vs -3.2 +/- 1.7%; p less than .05). A reduced neutrophil infiltrate was observed in the border zone in treated animals. These findings suggest that oxygen free radicals derived from the xanthine oxidase pathway contribute to stunning of reversibly damaged myocardium but do not determine the final extent of myocardial necrosis in a canine preparation of reperfusion.
Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart
Authors: M. Sameer Rana, Magali Théveniau-Ruissy, Christopher De Bono, Karim Mesbah, Alexandre Francou, Mayyasa Rammah, Jorge N. Domínguez, Marine Roux, Brigitte Laforest, Robert H. Anderson, Timothy Mohun, Stephane Zaffran, Vincent M. Christoffels, Robert G. Kelly
Journal: Circulation Research (2014)

Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the arterial pole of the heart, and atrial myocardium at the venous pole. Recent clonal analysis and cell-tracing experiments indicate that a common progenitor pool in the posterior region of the SHF gives rise to both OFT and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.To evaluate the role of TBX1, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.Using transcriptome analysis, genetic tracing, and fluorescent dye-labeling experiments, we show that Tbx1-dependent OFT myocardium originates in Hox-expressing cells in the posterior SHF. In Tbx1 null embryos, OFT progenitor cells fail to segregate from this progenitor cell pool, leading to failure to expand the dorsal pericardial wall and altered positioning of the cardiac poles. Unexpectedly, addition of SHF cells to the venous pole of the heart is also impaired, resulting in abnormal development of the dorsal mesenchymal protrusion, and partially penetrant atrioventricular septal defects, including ostium primum defects.Tbx1 is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents
Authors: Joel E. Lavine
Journal: JAMA (2011)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established.
Role of the QuantiFERON®-TB Gold In-Tube assay in screening new immigrants for tuberculosis infection
Authors: Christiaan Mulder, Henk van Deutekom, Erik M. Huisman, Sophie Toumanian, Ben F.P.J. Koster, Wieneke Meijer-Veldman, Joke H. van Loenhout-Rooyackers, Milo Appel, Sandra M. Arend, Martien W. Borgdorff, Frank van Leth
Journal: European Respiratory Journal (2012)

This study aimed to estimate the risk of progression to active tuberculosis (TB) within 2 yrs after entry in newly arriving immigrants who were screened with the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT; Cellestis, Carnegie, Australia). In a case–base design, we determined the prevalence QFT-GIT-positive subjects among a representative sample of immigrants aged ≥18 yrs who arrived between April 2009 and March 2011 (the base cohort). Active TB patients (cases) within 2 yrs post-arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register. The risk of progression to active TB was estimated using Bayesian analyses to adjust for the sensitivity of QFT-GIT. Among the base cohort, 20% of 1,468 immigrants were QFT-GIT positive. Stratified by TB incidence in the person's country of origin as low (&lt;100 cases per 100,000 population), intermediate (100–199 cases per 100,000) or high (≥200 cases per 100,000), the risk of progression to active TB per 100,000 arriving immigrants if QFT-GIT positive (95% credibility interval) was 456 (95% CI 307–589), 590 (397–762) and 386 (259–499), respectively, compared with 18 (0–46), 38 (0–97) and 28 (0–71) if QFT-GIT negative. Screening newly arriving immigrants with QFT-GIT contributes to detecting those at high risk of subsequent TB reactivation within 2 yrs after entry, which offers opportunities for prevention by targeted interventions.
THE METABOLISM OF COPPER AND IRON IN SPLENECTOMIZED RATS FREE FROM BARTONELLA MURIS INFECTION
Authors: Marta Sandberg, David Perla
Journal: The Journal of Experimental Medicine (1934)

Removal of the spleen in albino rats free from Bartonella muris infection is followed by an increased elimination of copper in the feces, which commences 2 weeks after splenectomy. This is associated with a persistent negative copper balance. An increased retention of iron occurs during a period of 4 to 6 weeks after splenectomy with a return of the iron metabolism to normal after this period. No disturbance in creatine or creatinine metabolism occurs. The uric acid amount is unchanged. There is an increase in the retention of nitrogen, which is first noted 3 weeks after splenectomy. The spleen is essential for the utilization of copper in the body.
Contrast-enhanced ultrasound in monitoring the efficacy of a bradykinin receptor 2 antagonist in painful knee osteoarthritis compared with MRI
Authors: I H Song, C E Althoff, K G Hermann, A K Scheel, T Knetsch, G R Burmester, M Backhaus
Journal: Annals of the Rheumatic Diseases (2008)

To evaluate contrast-enhanced ultrasound (CE-US) as a monitoring tool to assess hypervascularisation of synovial processes in knee osteoarthritis (OA) treated with intra-articular injections of the bradykinin-receptor 2 antagonist icatibant compared to contrast-enhanced magnetic resonance imaging (CE-MRI).In a randomised, double-blind, placebo-controlled trial, 41 patients with painful knee OA underwent US (12.5 MHz for B-mode and 3-8 MHz for CE-US), and 36 of the patients underwent additional MRI (0.2T) at baseline and after 3 injections of the study drug (after a mean of 22.2 days). A total of 15 patients received placebo (group A), 12 patients 500 microg icatibant (group B) and 14 patients 2000 microg icatibant (group C). Pain and the synovial process (B-mode, power Doppler US (PD-US), CE-US, CE-MRI) were assessed at both time points.At baseline, the placebo group showed more activity in terms of effusion in the superior and lateral recess in ultrasound as well as in PD-US in the lateral recess. Pain improved significantly in all subgroups. Effect sizes were 0.43 (pain at rest) and 0.52 (pain during activity) in group B vs 0.48 and 1.11 in group C. There was no change of US and MRI parameters. We found moderate to good correlation (r) and kappa values (kappa) for effusion in the superior recess (r = 0.591, k = 0.453), effusion in the lateral recess (r = 0.304, k = 0.440) and contrast enhancement (r = 0.601, k = 0.242) between US and MRI.Our results show that CE-US and CE-MRI have good agreement in assessing inflammatory changes in knee OA. For the 41 patients with OA, an analgesic effect of icatibant could clearly be shown, especially for pain during activity in the high dose icatibant group. However, we could not find an anti-inflammatory effect of icatibant by CE-US compared to CE-MRI.
<i>CCL2</i> Polymorphisms Are Associated With Serum Monocyte Chemoattractant Protein-1 Levels and Myocardial Infarction in the Framingham Heart Study
Authors: David H. McDermott, Qiong Yang, Sekar Kathiresan, L. Adrienne Cupples, Joseph M. Massaro, John F. Keaney, Martin G. Larson, Ramachandran S. Vasan, Joel N. Hirschhorn, Christopher J. O’Donnell, Philip M. Murphy, Emelia J. Benjamin
Journal: Circulation (2005)

Background— Monocyte chemoattractant protein-1 (MCP-1) is a chemokine strongly implicated in promoting atherosclerosis in animal models, but human genetic evidence is contradictory. Methods and Results— We analyzed the association of genetic variation in the MCP-1 gene ( CCL2 ) with prevalent myocardial infarction and serum MCP-1 levels in the community-based Framingham Heart Study Offspring Cohort (50% women; mean age, 62 years). MCP-1 levels and CCL2 genotypes were determined in 3236 and 1797 individuals, respectively. Significant clinical correlates of MCP-1 levels were age, cigarette smoking, triglycerides, body mass index, and waist-to-hip ratio. The MCP-1-2578G allele located in the CCL2 regulatory region was significantly associated with both higher serum MCP-1 levels in a recessive genetic model (358±10 versus 328±3 pg/mL; P =0.002) and higher prevalence of myocardial infarction in a dominant genetic model (adjusted odds ratio, 2.0; 95% CI, 1.2 to 3.3; P =0.005). We also defined the linkage disequilibrium structure at the CCL2 locus and observed 6 common haplotypes in whites. We performed haplotype-based association analysis and found that only the most frequent haplotype, defined by the MCP-1-2578G allele, was associated with prevalent MI. Conclusions— Our data are consistent with the hypothesis that MCP-1 is involved in the pathogenesis of human atherosclerosis and myocardial infarction.
Persistent Renal Damage After Contrast-Induced Acute Kidney Injury
Authors: Mauro Maioli, Anna Toso, Mario Leoncini, Michela Gallopin, Nicola Musilli, Francesco Bellandi
Journal: Circulation (2012)

The temporal evolution of renal function in patients with acute kidney injury after contrast medium (CI-AKI) is not well known. The aim of this observational study was to evaluate the incidence, risk factors, and prognostic implications of persistent renal damage (RD) in patients with preexistent moderate-to-severe renal dysfunction.From June 2003 to March 2008, 3986 patients underwent coronary angiography at our institution; 1490 of 3986 had an estimated creatinine clearance of <60 mL/min and were enrolled. CI-AKI was defined as an absolute increase ≥ 0.5 mg/dL over baseline serum creatinine within 3 days after the administration of contrast medium (iodixanol). In patients who developed CI-AKI, persistent RD was defined as a relative decrease of creatinine clearance ≥ 25% over baseline at 3 months. Patients whose creatinine clearance returned to baseline (or nearly) were classified as transient RD. The overall incidence of CI-AKI was 12.1%, and persistent RD occurred in 18.6% of CI-AKI patients. At Cox regression analysis, nephropathy risk score ≥ 17, left ventricular ejection fraction ≤ 30%, and increased value of serum creatinine ≥ 1.5-fold from baseline within 5 days were found to be significant risk factors for persistent RD. At 5 years, the incidence of death was significantly higher in patients with persistent RD than in both patients with transient RD (P=0.015) and those without CI-AKI (P=0.0001). A similar trend was observed for the combined end point of death, dialysis and cardiovascular events.These results suggest that CI-AKI is not always a transient, benign creatininopathy, but rather a direct cause of worsening renal function. The occurrence of CI-AKI can identify patients at increased risk of cardiovascular events.
Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats
Authors: Aysar Al Husseini, Gianluca Bagnato, Laszlo Farkas, Jose Gomez-Arroyo, Daniela Farkas, Shiro Mizuno, Donatas Kraskauskas, Antonio Abbate, Benjamin Van Tassel, Norbert F. Voelkel, Harm Jan Bogaard
Journal: European Respiratory Journal (2012)

Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of α v β 3 integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined.
Interactions of the Classical and Alternate Complement Pathway with Endotoxin Lipopolysaccharide EFFECT ON PLATELETS AND BLOOD COAGULATION
Authors: Michael A. Kane, Joseph E. May, Michael M. Frank
Journal: Journal of Clinical Investigation (1973)

The contributions of the classical and alternate pathways of complement activation to the biological effects of endotoxin have been examined in the guinea pig, with particular reference to thrombocytopenia, leukopenia, and the development of the hypercoagulable state. Injection of endotoxin into normal guinea pigs led to a 95% fall in the level of circulating platelets within 15 min as well as a fall in circulating granulocytes. C4-deficient guinea pigs, known to have a complete block in the activity of the classical complement pathway, but with the alternate pathway intact, sustained no fall in platelets. The development of granulocytopenia proceeded normally. Endotoxin did activate the alternate complement pathway in C4D guinea pigs, as evidenced by the fall in C3-9 titers. With restoration of serum C4 levels, endotoxin-induced thrombocytopenia was observed in C4D animals. Thus, function of the classical complement pathway was an absolute requirement for the development of thrombocytopenia. Experiments performed in cobra venom factor (CVF)-treated normal guinea pigs, with normal levels of C1, C4, and C2, but with less than 1% of serum C3-9 demonstrated the importance of the late components in the development of thrombocytopenia but not leukopenia.C4-deficient guinea pigs had normal clotting times demonstrating that C4 was not required for normal clotting. In addition, development of the hypercoagulable state, evidenced by a marked shortening of the clotting time, was not observed on injection of endotoxin into C4D animals. Therefore, development of the hypercoagulable state paralleled the development of thrombocytopenia and required function of the classical complement pathway. Again, the importance of the late components of complement was emphasized by the failure of CVF-treated normal animals to develop hypercoagulability. These results demonstrate that endotoxin is capable of activating both the classical and alternate complement pathways in guinea pigs but that function of the classical pathway is an absolute requirement for the development of thrombocytopenia and the hypercoagulable state.
A Twelve-Year Follow-Up of New York Narcotic Addicts: IV. Some Characteristics and Determinants of Abstinence
Authors: GEORGE E. VAILLANT
Journal: American Journal of Psychiatry (1966)

Thirty urban narcotic addicts who over a 12-year period achieved stable abstinences were compared with 30 chronic addicts. Abstinence was associated with certain changes in defensive style but did not result in emergence of new psychiatric symptomatology. It occurred most often in addicts with a prior history of regular employment and a stable early childhood. Compulsory community supervision, discovery of substitutes for narcotics, and gratifying nonfamily object relationships appeared to be important factors in producing abstinence.
Nitrosative modifications of the Ca<sup>2+</sup>release complex and actin underlie arthritis-induced muscle weakness
Authors: Takashi Yamada, Olga Fedotovskaya, Arthur J Cheng, Anabelle S Cornachione, Fabio C Minozzo, Cecilia Aulin, Cecilia Fridén, Carl Turesson, Daniel C Andersson, Birgitta Glenmark, Ingrid E Lundberg, Dilson E Rassier, Håkan Westerblad, Johanna T Lanner
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca<sup>2+</sup> handling and specific force production. <h3>Methods</h3> Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca<sup>2+</sup> release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers. <h3>Results</h3> The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca<sup>2+</sup>]<sub>i</sub> during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca<sup>2+</sup>]<sub>i</sub>, individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin. <h3>Conclusions</h3> Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca<sup>2+</sup> activation.
UK government's delay on plain tobacco packaging: how much evidence is enough?
Authors: C. Moodie, L. Bauld, M. Stead
Journal: BMJ (2013)

Early findings from Australia add to a rapidly growing body of research

In the wake of the UK government’s announcement on 12 July that its decision on plain (standardised) tobacco packaging would be delayed until evidence emerged from Australia, Wakefield and colleagues report timely findings from a study exploring the early effects of plain packaging in Victoria.1 2 Conducted during the phase-in period, when plain and branded packs were concurrently on sale, the study found that smokers who used plain packs were more likely than smokers who used fully branded packs to perceive their cigarettes to be less satisfying and poorer quality, were more supportive of plain packaging, and were more likely to think about and to prioritise quitting.

These findings extend what was already known about standardised packaging but in a market where plain packs are now on sale. That the appearance of packs influenced users’ perceptions of the products is supported by the systematic review commissioned to inform the UK government’s consultation on standardised packaging,3 as well as …
Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse
Authors: Michael J. Brennick, Allan I. Pack, Kei Ko, Eugene Kim, Stephen Pickup, Greg Maislin, Richard J. Schwab
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

The effect of obesity on upper airway soft tissue structure and size was examined in the New Zealand Obese (NZO) mouse and in a control lean mouse, the New Zealand White (NZW).
A Novel Approach for Developing and Interpreting Treatment Moderator Profiles in Randomized Clinical Trials
Authors: Meredith L. Wallace, Ellen Frank, Helena C. Kraemer
Journal: JAMA Psychiatry (2013)

<h3>Importance</h3> Identifying treatment moderators may help mental health practitioners arrive at more precise treatment selection for individual patients and can focus clinical research on subpopulations that differ in treatment response. <h3>Objective</h3> To demonstrate a novel exploratory approach to moderation analysis in randomized clinical trials. <h3>Design, Setting, and Participants</h3> A total of 291 adults from a randomized clinical trial that compared an empirically supported psychotherapy with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy as treatments for depression. <h3>Main Outcomes and Measures</h3> We selected 8 relatively independent individual moderators out of 32 possible variables. A combined moderator,<i>M*</i>, was developed as a weighted combination of the 8 selected individual moderators.<i>M*</i>was then used to identify individuals for whom psychotherapy may be preferred to SSRI pharmacotherapy or vice versa. <h3>Results</h3> Among individual moderators, psychomotor activation had the largest moderator effect size (0.12; 95% CI, &lt;.01 to 0.24). The combined moderator,<i>M*</i>, had a larger moderator effect size than any individual moderator (0.31; 95% CI, 0.15 to 0.46). Although the original analyses demonstrated no overall difference in treatment response,<i>M*</i>divided the study population into 2 subpopulations, with each showing a clinically significant difference in response to psychotherapy vs SSRI pharmacotherapy. <h3>Conclusions and Relevance</h3> Our results suggest that the strongest determinations for personalized treatment selection will likely require simultaneous consideration of multiple moderators, emphasizing the value of the methods presented here. After validation in a randomized clinical trial, a mental health practitioner could input a patient's relevant baseline values into a handheld computer programmed with the weights needed to calculate<i>M*</i>. The device could then output the patient's<i>M*</i>value and suggested treatment, thereby allowing the mental health practitioner to select the treatment that would offer the greatest likelihood of success for each patient.