tbuckley/cabot-search huggingface dataset:
Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer
Authors: Ujjal Mallick, Clive Harmer, Beng Yap, Jonathan Wadsley, Susan Clarke, Laura Moss, Alice Nicol, Penelope M Clark, Kate Farnell, Ralph McCready, James Smellie, Jayne A Franklyn, Rhys John, Christopher M Nutting, Kate Newbold, Catherine Lemon, Georgina Gerrard, Abdel Abdel-Hamid, John Hardman, Elena Macias, Tom Roques, Stephen Whitaker, Rengarajan Vijayan, Pablo Alvarez, Sandy Beare, Sharon Forsyth, Latha Kadalayil, Allan Hackshaw
Journal: New England Journal of Medicine (2012)

It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal.At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay.A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11).Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).
Intercellular communication lessons in heart failure
Authors: Claudia Bang, Charalambos Antoniades, Alexios S. Antonopoulos, Ulf Eriksson, Constantijn Franssen, Nazha Hamdani, Lorenz Lehmann, Christine Moessinger, Marco Mongillo, Lars Muhl, Thimoteus Speer, Thomas Thum
Journal: European Journal of Heart Failure (2015)
Time to walk the talk: embracing the built environment to promote physical mobility
Authors: Lawrence D Frank, Heather A McKay
Journal: British Journal of Sports Medicine (2010)

In Outliers, Malcolm Gladwell argued that ‘success’—whether it be sporting, financial or health-related—resulted not from genetic mutation but from an environment that provides some substantial advantage.1 In this Warm up, we draw attention to the Built Environment as an overlooked determinant of health.2,–,4 Remember, the built environment—the places in which people live, work and play—is the setting for your patients to execute your activity prescription!

People who rely only on ‘recreational or leisure time’ to battle the epidemic of physical inactivity usually lose. Time to recreate is constrained by many factors including increasing time required to travel and work.5 On the other hand, those who walk to the bus or train, who walk to shops in their local community and who bike to work are likely to meet physical activity guidelines.6 7 A built environment that supports walking, biking and transit over driving can help to structure daily patterns to include regular physical activity. A transit trip is an interrupted walk trip—one study found that, …
Role of clinical pathologies in myocardial injury following ischaemia and reperfusion
Authors: M Galiñanes
Journal: Cardiovascular Research (2003)

The myocardial injury that occurs following a period of ischaemia and reperfusion is well recognised and the underlying mechanisms have been extensively investigated in healthy myocardial tissues; however, the influence of the risk factors associated with cardiovascular diseases on ischaemia/reperfusion injury remains unclear. In this article, the present knowledge on how clinical pathologies such as diabetes, hypercholesterolaemia, hypertension, myocardial hypertrophy and heart failure may influence ischaemia/reperfusion injury of the heart and the potential mechanisms involved are reviewed.
Anti-β1AR antibodies in dilated cardiomyopathy: Are these a new class of receptor agonists?
Authors: T HEBERT
Journal: Cardiovascular Research (2007)

See article by Tutor et al.  [9]  (pages 51−60) in this issue. 

Under physiological conditions, the β1-adrenergic receptor (β1AR) is the predominant βAR responsible for inotropic, chronotropic and lusitropic responses in the myocardium via the classical Gs/adenylyl cyclase/PKA pathway (reviewed in [1–3]). However, during the development of heart failure, sustained β1AR signalling may also lead to a number of adverse effects including cardiomyocyte hypertrophy and eventually apoptosis. It has become clear in recent years that alterations in the ERK and other MAP kinase signalling cascades play critical and complicated roles in the development of cardiac hypertrophy and the progression towards heart failure [4]. It is also clear that β-adrenergic receptors are key regulators of MAP kinase signalling, especially in the context of heart disease [5]. In a series of interesting papers, Martin Lohse and his colleagues have demonstrated a causal role in disease progression for autoimmune anti-β1AR antibodies found in patients with dilated cardiomyopathy (DCM, [6–8]). In an article in this issue of Cardiovascular Research , Tutor et al. [9] demonstrate a novel link between all of these observations by showing that anti-β1AR antibodies from several patients with DCM, but not control sera from healthy donors or sera from DCM patients that do not produce anti-β1AR, can activate the ERK signalling pathway in a manner distinct from receptor ligands. Their study has significant implications for basic receptor … 

*Tel.: +1 514 398 1398; fax: +1 514 398 6690. terence.hebert{at}mcgill.ca
Open Surgical Repair Versus Endovascular Therapy for Chronic Lower-Extremity Occlusive Disease
Authors: Marc L. Schermerhorn, Jack L. Cronenwett, John C. Baldwin
Journal: Annual Review of Medicine (2003)

Chronic lower-extremity occlusive disease is most often manifested by mild symptoms of claudication that can be managed conservatively. When conservative therapy fails, endovascular procedures may be effective, particularly if the disease extent is minimal. Surgery may be considered for selected patients with claudication who fail endovascular therapy or are not candidates for it. Patients with more severe symptoms of lower-extremity occlusive disease typically have more extensive disease that is treated best with surgery or with a combination of surgery and endovascular therapy. Occasionally, endovascular procedures are performed on patients with more extensive disease who are poor candidates for traditional open surgery because of severe comorbidity. Further advances in endovascular technology may improve patency after endovascular procedures in these patients.
Prodigies of nature
Authors: J S Jenkins
Journal: Journal of the Royal Society of Medicine (2005)

On 31 May 1764 the following notice appeared in the London Public Advertiser:


'At the Great Room in Spring Garden, near St James' Park, Tuesday June 5, will be performed a grand concert of vocal and instrumental music. For the benefit of Miss Mozart of eleven and Master Mozart of seven years of age, Prodigies of Nature; taking the opportunity of representing to the public the greatest prodigy that Europe or that human nature has to boast of. Everybody will be astonished to hear a child of such a tender age playing the harpsichord in such perfection—it surmounts all fantastic imagination and it is hard to express which is more astounding, his execution upon the harpsichord playing at sight or his own compositions.'1


Even when we allow for Leopold Mozart's hyperboles and the fact that he deducted a year from his children's ages, young Wolfgang was clearly one of the great musical prodigies.

Prodigies have always been regarded with awe because they disobey the usual rules of childhood development. A study of their lives shows that various factors are involved in the determination of their extraordinary achievements. High ability may be linked to creativity but what is most easily measured is performance.
Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development in Apolipoprotein E–Deficient Mice Challenged With a High-Fat Diet
Authors: Sean C. Harrington, Robert D. Simari, Cheryl A. Conover
Journal: Circulation Research (2007)

Pregnancy-associated plasma protein–A (PAPP-A), a metalloproteinase in the insulin-like growth factor (IGF) system, is markedly upregulated in human atherosclerotic plaque. To determine whether PAPP-A plays an active role in the development of atherosclerosis, we crossed mice lacking apolipoprotein E (ApoE) with PAPP-A–deficient mice, generating ApoE knock-out (KO), PAPP-A KO, wild-type (WT/WT), and ApoE/PAPP-A double KO (KO/KO) mice. These mice were fed a high-fat diet starting at 7 weeks of age. Total serum cholesterol levels were elevated similarly in the ApoE KO and KO/KO mice and were 10-fold higher than in the WT/WT and PAPP-A KO mice. WT/WT and PAPP-A KO mice showed little or no lesion development even after 20 weeks of diet. ApoE KO mice had a progressive increase in aortic lesion area over 20 weeks of diet. In comparison, lesion area was reduced 60% to 80% in KO/KO mice. Lesions of ApoE KO aortas had 8- to 20-fold increases in PAPP-A, IGFBP-4, and IGF-I mRNA levels compared with nonlesional areas, whereas IGF-I receptor levels were equivalent—conditions for enhanced lesional IGF activity. Consistent with this, an in vivo marker of IGF-I receptor-mediated action was increased 10-fold in lesions from ApoE KO compared with KO/KO aortas. These data indicate that PAPP-A plays a critical role in lesion development in a mouse model of atherosclerosis, at least in part, through amplification of local IGF-I bioavailability.
Effect of Lipohypertrophy on Accuracy of Continuous Glucose Monitoring in Patients With Type 1 Diabetes
Authors: Daniel J. DeSalvo, David M. Maahs, Laurel Messer, R. Paul Wadwa, Shelby Payne, Trang T. Ly, Bruce A. Buckingham
Journal: Diabetes Care (2015)

Repeated delivery of insulin in the same location induces a local reaction in the subcutaneous adipose tissue, often leading to lipohypertrophy (1,2). Advanced lipohypertrophy leads to slower, erratic insulin absorption due to the fibrous, relatively avascular nature of the tissue (3). Although lipohypertrophied tissue is commonly used for continuous glucose monitoring (CGM) sensor sites, the effect on sensor performance is unknown. Therefore, we analyzed the accuracy of sensors used simultaneously in lipohypertrophied and normal tissue.

In this prospective, multicenter study, subjects with type 1 diabetes and lipohypertrophy (≥3 cm diameter) were instructed to wear two Dexcom G4 Platinum sensors simultaneously: one in lipohypertrophied tissue and the second in normal tissue for 2 consecutive weeks. This procedure was then repeated on each subject with new sensors being worn simultaneously for a second 2-week period. Blood glucose (BG) readings from Bayer CONTOUR NEXT meters served as reference (4), with absolute …
Analysis of Protease Activity Using Quantum Dots and Resonance Energy Transfer
Authors: Gae Baik Kim, Young-Pil Kim
Journal: Theranostics (2012)

This review demonstrates the detection of protease activity based on the energy transfer of quantum dots (QDs). By incorporation of varying protease substrates into designed QD probes both in fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) system, proteolytic activity led to changes in the energy transfer efficiency. Especially due to the superior properties of QDs, it can be served as an excellent probe for a multiplexed and high-throughput protease assay with high sensitivity. It is anticipated that the QD-based FRET/BRET probes will have a great potential for dissecting the fundamental roles of proteases and designing potential protease inhibitors as therapeutic drugs in biology and nanomedicine.
Blood Pressure-Independent Additive Effects of Pharmacologic Blockade of the Renin-Angiotensin and Endothelin Systems on Progression in a Low-Renin Model of Renal Damage
Authors: Kerstin Amann, Aurelia Simonaviciene, Tatiana Medwedewa, Andreas Koch, Stephan Orth, Marie-Luise Gross, Christian Haas, Alexander Kuhlmann, Wolfgang Linz, Bernward Schölkens, Eberhard Ritz
Journal: Journal of the American Society of Nephrology (2001)

Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ET(A) receptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 +/- 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 +/- 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 +/- 0.06), compared with AT1-RA (0.60 +/- 0.10) or ET-RA (0.65 +/- 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 +/- 0.09) or AT1-RA plus ET-RA (23 +/- 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.
Clara cells drive eosinophil accumulation in allergic asthma
Authors: S.S. Sonar, M. Ehmke, L.M. Marsh, J. Dietze, J.C. Dudda, M.L. Conrad, H. Renz, W.A. Nockher
Journal: European Respiratory Journal (2011)

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the “immunomodulatory barrier” of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 μg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion. Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung. These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.
The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin.
Authors: D L Clemens, M A Horwitz
Journal: The Journal of Experimental Medicine (1996)

Previous studies have demonstrated that the Mycobacterium tuberculosis phagosome in human monocyte-derived macrophages acquires markers of early and late endosomes, but direct evidence of interaction of the M. tuberculosis phagosome with the endosomal compartment has been lacking. Using the cryosection immunogold technique, we have found that the M. tuberculosis phagosome acquires exogenously added transferrin in a time-dependent fashion. Near-maximal acquisition of transferrin occurs within 15 min, kinetics of acquisition consistent with interaction of the M. tuberculosis phagosome with early endosomes. Transferrin is chased out of the M. tuberculosis phagosome by incubation of the infected macrophages in culture medium lacking human transferrin. Phagosomes containing latex beads or heat-killed M. tuberculosis, on the other hand, do not acquire staining for transferrin. These and other findings demonstrate that M. tuberculosis arrests the maturation of its phagosome at a stage at which the phagosome interacts with early and late endosomes, but not with lysosomes. The transferrin endocytic pathway potentially provides a novel route for targeting antimicrobials to the M. tuberculosis phagosome.
One more reason to save your hair
Authors: D. Scholz, S. Ergun
Journal: Cardiovascular Research (2008)

Hair follicles are self-renewing structures that cycle and reconstitute themselves throughout life because they contain keratinocyte stem cells.1 After new evidence has been presented about hair follicle cells differentiating into adipogenic, osteogenic, chondrogenic, myogenic, neuronal, and glial2–5 lineages, the question arises whether these cell possess other abilities and whether they are pluri- or even omnipotent. In this context, the work by Liu et al. 6 in this issue of Cardiovascular Research inserts an important piece into the hair follicle puzzle. It presents clear evidence for the conversion of hair follicle stem cells into smooth muscle cells that have the ability to contract.

The construction of functional tissue-engineered blood vessels from progenitor cells is a declared goal for this group.6,7 Lack of availability of autologous vascular grafts and the pain and discomfort associated with the donor site necessitate the development of tissue-engineered blood vessels for tissue regeneration. One of the major challenges is to get an easily accessible, autologous source of progenitor cells. The hair follicle seems to be a lucky … 

*Corresponding author. Tel: +1 353 716 6958. E-mail address: dimitri.scholz{at}ucd.ie
Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides: A randomized controlled trial
Authors: Karin E. Koopman, Matthan W.A. Caan, Aart J. Nederveen, Anouk Pels, Mariette T. Ackermans, Eric Fliers, Susanne E. la Fleur, Mireille J. Serlie
Journal: Hepatology (2014)

American children consume up to 27% of calories from high-fat and high-sugar snacks. Both sugar and fat consumption have been implicated as a cause of hepatic steatosis and obesity but the effect of meal pattern is largely understudied. We hypothesized that a high meal frequency, compared to consuming large meals, is detrimental in the accumulation of intrahepatic and abdominal fat. To test this hypothesis, we randomized 36 lean, healthy men to a 40% hypercaloric diet for 6 weeks or a eucaloric control diet and measured intrahepatic triglyceride content (IHTG) using proton magnetic resonance spectroscopy ( 1 H-MRS), abdominal fat using magnetic resonance imaging (MRI), and insulin sensitivity using a hyperinsulinemic euglycemic clamp with a glucose isotope tracer before and after the diet intervention. The caloric surplus consisted of fat and sugar (high-fat-high-sugar; HFHS) or sugar only (high-sugar; HS) and was consumed together with, or between, the three main meals, thereby increasing meal size or meal frequency. All hypercaloric diets similarly increased body mass index (BMI). Increasing meal frequency significantly increased IHTG (HFHS mean relative increase of 45%; P = 0.016 and HS mean relative increase of 110%; P = 0.047), whereas increasing meal size did not (2-way analysis of variance [ANOVA] size versus frequency P = 0.03). Abdominal fat increased in the HFHS-frequency group (+63.3 ± 42.8 mL; P = 0.004) and tended to increase in the HS-frequency group (+46.5 ± 50.7 mL; P = 0.08). Hepatic insulin sensitivity tended to decrease in the HFHS-frequency group while peripheral insulin sensitivity was not affected. Conclusion : A hypercaloric diet with high meal frequency increased IHTG and abdominal fat independent of caloric content and body weight gain, whereas increasing meal size did not. This study suggests that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis and obesity. (Trial registration: www.clinicaltrials.gov; nr.NCT01297738.) (Hepatology 2014;60:545–553)
Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery
Authors: Thomas Reinert, Lone V Schøler, Rune Thomsen, Heidi Tobiasen, Søren Vang, Iver Nordentoft, Philippe Lamy, Anne-Sofie Kannerup, Frank V Mortensen, Katrine Stribolt, Stephen Hamilton-Dutoit, Hans J Nielsen, Søren Laurberg, Niels Pallisgaard, Jakob S Pedersen, Torben F Ørntoft, Claus L Andersen
Journal: Gut (2015)

<h3>Objective</h3> To develop an affordable and robust pipeline for selection of patient-specific somatic structural variants (SSVs) being informative about radicality of the primary resection, response to adjuvant therapy, incipient recurrence and response to treatment performed in relation to diagnosis of recurrence. <h3>Design</h3> We have established efficient procedures for identification of SSVs by next-generation sequencing and subsequent quantification of 3–6 SSVs in plasma. The consequence of intratumour heterogeneity on our approach was assessed. The level of circulating tumour DNA (ctDNA) was quantified in 151 serial plasma samples from six relapsing and five non-relapsing colorectal cancer (CRC) patients by droplet digital PCR, and correlated to clinical findings. <h3>Results</h3> Up to six personalised assays were designed for each patient. Our approach enabled efficient temporal assessment of disease status, response to surgical and oncological intervention, and early detection of incipient recurrence. Our approach provided 2–15 (mean 10) months9 lead time on detection of metastatic recurrence compared to conventional follow-up. The sensitivity and specificity of the SSVs in terms of detecting postsurgery relapse were 100%. <h3>Conclusions</h3> We show that assessment of ctDNA is a non-invasive, exquisitely specific and highly sensitive approach for monitoring disease load, which has the potential to provide clinically relevant lead times compared with conventional methods. Furthermore, we provide a low-coverage protocol optimised for identifying SSVs with excellent correlation between SSVs identified in tumours and matched metastases. Application of ctDNA analysis has the potential to change clinical practice in the management of CRC.