tbuckley/cabot-search huggingface dataset:
Back to the future: republishing Bradford Hill and more from our archive
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2015)

We look ahead to 2015 by looking back 50 years. Any historian will tell you that the answers to our current problems can be found in events of the past. The pace of medical advance makes this concept difficult to apply to current clinical practice but last month's JRSM gave the example of the relevance of John Haygarth's work in the 18th century to our present difficulties in dealing with Ebola.1

The Journal of the Royal Society of Medicine has been continuously published in various guises since 1809. It was a journal before The BMJ and The Lancet came into existence. The journal has had other names. It began as Medico-Chirurgical Transactions, and with the formation of the Royal Society of Medicine in 1907 changed name to Proceedings of the Royal Society of Medicine. This name better reflected the role of the journal in reporting on momentous presentations at the RSM. The focus of Proceedings was very much on the clinical debates and lectures at the society.

But medicine changed. International meetings are now the forum for announcing clinical breakthroughs. The RSM has a different role, focused on education, updating specialists on the latest developments in the world of medicine and not just events at Wimpole Street. The journal has changed accordingly, and as the Journal of the Royal Society of Medicine it seeks to educate and inform a multispecialty readership, and publish important new research of relevance to its readers. As such, the articles in JRSM don't often arise from meetings at RSM, although such articles are happily considered for publication.

Historical pieces were once a mainstay of this journal. When I started as editor I made the decision to cover less medical history to leave space for content of more direct relevance to current clinical practice and health policy. There is still room though for interesting historical pieces, as a quick browse through last year's issues will confirm. Indeed, our regular section from the James Lind Library is a treasure trove of historical developments in clinical research.2

Last year, the complete back archive of JRSM dating back to 1809 was made available on the journal's website.3 Thanks to our access policy, the vast majority of this rich content is free. The pages of the journal tell the story of the major events in medicine and allow us to reflect on the challenges faced by our clinical colleagues from a different age. We might learn from their experiences.

In appreciation of this history we start a new feature that will each month republish a piece from the JRSM of 50 years ago. We begin with a landmark article by Austin Bradford Hill on association and causation in epidemiology.4 An accompanying editorial by Richard Wakeford explains its importance.5 Wakeford argues that Bradford Hill's article remains of relevance today, perhaps more so than ever, and proposes that it should be required reading for the medical profession and beyond.
Role of Insulin-like Growth Factor Binding Protein-3 in Allergic Airway Remodeling
Authors: Kristen L. Veraldi, Bethany T. Gibson, Hidekata Yasuoka, Michael M. Myerburg, Elizabeth A. Kelly, Silvana Balzar, Nizar N. Jarjour, Joseph M. Pilewski, Sally E. Wenzel, Carol A. Feghali-Bostwick
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: The hallmarks of allergic asthma are airway inflammation, obstruction, and remodeling. Airway remodeling may lead to irreversible airflow obstruction with increased morbidity and mortality. Despite advances in the treatment of asthma, the mechanisms underlying airway remodeling are still poorly understood. We reported that insulin-like growth factor (IGF) binding proteins (IGFBPs) contribute to extracellular matrix deposition in idiopathic pulmonary fibrosis; however, their contribution to airway remodeling in asthma has not been established.Objectives: We hypothesized that IGFBP-3 is overexpressed in asthma and contributes to airway remodeling.Methods: We evaluated levels of IGFBP-3 in tissues and bronchoalveolar lavage fluid from patients with asthma at baseline and 48 hours after allergen challenge, in reparative epithelium in an in vitro wounding assay, and in conditioned media from cytokine- and growth factor–stimulated primary epithelial cells.Measurements and Main Results: IGFBP-3 levels and distribution were evaluated by Western blot, ELISA, and immunofluorescence. IGFBP-3 is increased in vivo in the airway epithelium of patients with asthma compared with normal control subjects. The concentration of IGFBP-3 is increased in the bronchoalveolar lavage fluid of patients with asthma after allergen challenge, its levels are increased in reparative epithelium in an in vitro wounding assay and in the conditioned medium of primary airway epithelial cell cultures stimulated with IGF-I.Conclusions: Our results suggest that one mechanism of allergic airway remodeling is through the secretion of the profibrotic IGFBP-3 from IGF-I–stimulated airway epithelial cells during allergic inflammation.
Paracetamol and asthma
Authors: G KARAKAYA
Journal: Thorax (2001)

We were interested to read the article by Shaheen et al on the relationship between paracetamol and asthma.1 We have been interested in patients with analgesic induced asthma (AIA) since 1991 and now have a total of about 238 patients who have been followed up in our allergy unit. We have previously reported some related allergic conditions and risk factors for AIA, one of which was cumulative life long analgesic consumption.2-4 After reading the paper by Shaheen et al we re-analysed our data and compared the …
Association analysis of oestrogen receptor beta gene ( <i>ESR2</i> ) polymorphisms with female pattern hair loss
Authors: L. Yip, S. Zaloumis, D. Irwin, G. Severi, J. Hopper, G. Giles, S. Harrap, R. Sinclair, J. Ellis
Journal: British Journal of Dermatology (2011)

Funding sources: we gratefully acknowledge Epiderm (formerly the Australasian Dermatology Research and Education Foundation) for funding this study. The Melbourne Collaborative Cohort Study is supported by the Australian National Health and Medical Research Council (NHMRC) (grants 209057, 251533, 396414, 504711). Cohort recruitment and follow‐up is funded by The Cancer Council Victoria. J.A.E. is supported by a NHMRC capacity building grant in population health. Conflicts of interest: none declared. Madam, Recently, we reported an association of female pattern hair loss (FPHL) with polymorphism of the gene encoding aromatase (CYP19A1),1 the enzyme that converts androgens to oestrogens. The same polymorphism had previously been associated with higher oestrogen levels in postmenopausal women.2 Our findings therefore suggested that oestrogen might be important in FPHL risk. We now extend our previous work to include ESR2, encoding oestrogen receptor beta,3 the predominant oestrogen receptor within the hair follicle, and thought to be the principal mediator of oestrogenic effects in hair growth.4
Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia
Authors: Bing Li, Robert Peter Gale, Zhijian Xiao
Journal: Journal of Hematology & Oncology (2014)

According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis.
The Combination of a Histone Deacetylase Inhibitor with the Bcl-2 Homology Domain-3 Mimetic GX15-070 Has Synergistic Antileukemia Activity by Activating Both Apoptosis and Autophagy
Authors: Yue Wei, Tapan Kadia, Weigang Tong, Ming Zhang, Yu Jia, Hui Yang, Yumin Hu, Francesco Paolo Tambaro, Jean Viallet, Susan O'Brien, Guillermo Garcia-Manero
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Single-agent histone deacetylase inhibitors (HDACi) have limited clinical activity in human leukemia. Although the way HDACi exert their antileukemia effect is not fully understood, it is accepted that induction of apoptosis is important. We hypothesized, therefore, that combination of an HDACi with a proapoptotic agent, such as the Bcl-2 homology domain-3 mimetic GX15-070, could result in enhanced antileukemia activity. Experimental Design: We analyzed the cellular and molecular effects of two different HDACi (MGCD0103 and vorinostat) in combination with GX15-070 in leukemia cell lines and primary acute myelogenous leukemia cells. Results: We showed that the combination had synergistic antileukemia effect both in leukemia cell lines and in primary acute myelogenous leukemia cells. Using molecular markers and electron microscopy, we observed that in addition to apoptosis, autophagy accounts for the nonapoptotic decrease in cell viability, an effect that could be inhibited by chloroquine, an inhibitor of autophagy. Finally, we established a role for calpain activity in the induction of both autophagy and apoptosis by this combination. Conclusions: The combination of an HDACi and GX15-070 has synergistic antileukemia activity, and the effect is mediated by induction of apoptosis and autophagy. The combination should be studied in clinical trials of leukemia and the role of autophagy in leukemia therapy needs to be better understood. Clin Cancer Res; 16(15); 3923–32. ©2010 AACR.
Annular telangiectatic perivascular angiomatosis: a paradoxical adverse event of propranolol
Authors: J.E. Ollague Sierra, J.M. Ollague Torres
Journal: British Journal of Dermatology (2013)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, An 83‐year‐old woman presented with a 4‐month history of asymptomatic annular lesions, with disseminated distribution except for the face and distal part of the extremities. They were characterized by erythemato‐violaceous and somewhat hyperpigmented, annular plaques with central clearing and radial telangiectasias (Fig. 1). These were sharply demarcated, slightly raised with a smooth surface. The diameter ranged between 3 and 8 cm. Her past medical history included hypertension for the previous 12 years, controlled with propranolol 100 mg daily for the last 5 years. One biopsy from the chest and another from the left lumbar area were obtained. Histology in both revealed a superficial, mid and deep perivascular angiomatous proliferation with a glomerulus‐like appearance (Fig. 2) and absent inflammatory infiltrate. Some dilated bloodless vessels were present in the superficial and mid‐reticular dermis. The epidermis and adnexa were normal. Immunohistochemistry for CD34 was performed, with positive staining.
Uncoupled Cardiac Nitric Oxide Synthase Mediates Diastolic Dysfunction
Authors: Gad A. Silberman, Tai-Hwang M. Fan, Hong Liu, Zhe Jiao, Hong D. Xiao, Joshua D. Lovelock, Beth M. Boulden, Julian Widder, Scott Fredd, Kenneth E. Bernstein, Beata M. Wolska, Sergey Dikalov, David G. Harrison, Samuel C. Dudley
Journal: Circulation (2010)

Heart failure with preserved ejection fraction is 1 consequence of hypertension and is caused by impaired cardiac diastolic relaxation. Nitric oxide (NO) is a known modulator of cardiac relaxation. Hypertension can lead to a reduction in vascular NO, in part because NO synthase (NOS) becomes uncoupled when oxidative depletion of its cofactor tetrahydrobiopterin (BH(4)) occurs. Similar events may occur in the heart that lead to uncoupled NOS and diastolic dysfunction.In a hypertensive mouse model, diastolic dysfunction was accompanied by cardiac oxidation, a reduction in cardiac BH(4), and uncoupled NOS. Compared with sham-operated animals, male mice with unilateral nephrectomy, with subcutaneous implantation of a controlled-release deoxycorticosterone acetate pellet, and given 1% saline to drink were mildly hypertensive and had diastolic dysfunction in the absence of systolic dysfunction or cardiac hypertrophy. The hypertensive mouse hearts showed increased oxidized biopterins, NOS-dependent superoxide production, reduced NO production, and dephosphorylated phospholamban. Feeding hypertensive mice BH(4) (5 mg/d), but not treating with hydralazine or tetrahydroneopterin, improved cardiac BH(4) stores, phosphorylated phospholamban levels, and diastolic dysfunction. Isolated cardiomyocyte experiments revealed impaired relaxation that was normalized with short-term BH(4) treatment. Targeted cardiac overexpression of angiotensin-converting enzyme also resulted in cardiac oxidation, NOS uncoupling, and diastolic dysfunction in the absence of hypertension.Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction.
Mechanism of hyperreninemia in the potassium-depleted rat.
Authors: S L Linas
Journal: Journal of Clinical Investigation (1981)

Although dietary potassium deficiency (KD) results in an increase in plasma renin activity (PRA), the mechanism of this effect has not been elucidated. In the present study, isolated kidneys from normal rats or from rats made KD by diet were perfused at constant pressure (120 mm Hg) with a Krebs-Ringer-Bicarbonate medium containing albumin. KD led to an increase in PRA (3.6 vs. 1.1 ng angiotensin I ml per h, P less than 0.01), which was associated with a decrease in macula densa (MD) fluid delivery as estimated by urine flow (70 vs. 166 microliters/min per g, P less than 0.005), and an increase in renal vascular resistance (RVR) as perfusion flow rate was decreased from 34 to 24 ml/min per g, P less than 0.005. The increase in PRA was independent of the MD because PRA could not be suppressed when macula densa delivery was increased by perfusing KD kidneys with hypooncotic albumin. Moreover, when kidneys were made nonfiltering by perfusing with hyperconcotic albumin, PRA remained increased in KD kidneys (8.1 vs. 3.5 ng angiotensin I ml per h, P less than 0.01) despite the absence of MD delivery. Because the increase in PRA in both filtering and nonfiltering KD kidneys was associated with an increase in RVR, filtering and nonfiltering kidneys were perfused with the vasodilator papaverine. Despite lower tissue K levels in KD kidneys (278 vs. 357 mu eq/g, P less than 0.01), RVR and PRA were normalized in both filtering and nonfiltering KD kidneys perfused with papaverine. In conclusion, PRA is increased in the KD isolated perfused kidney. This increase occurs independently of both the MD and of tissue K levels and is mediated by the renal vascular receptor.
Tungstate activates BK channels in a β subunit- and Mg2+-dependent manner: relevance for arterial vasodilatation
Authors: Ana I. Fernández-Mariño, Cristina Porras-González, Patricia González-Rodríguez, Jana Selent, Manuel Pastor, Juan Ureña, Antonio Castellano, Miguel A. Valverde, José M. Fernández-Fernández
Journal: Cardiovascular Research (2012)

AimsTungstate reduces blood pressure in experimental animal models of both hypertension and metabolic syndrome, although the underlying mechanisms are not fully understood. Given that the large-conductance voltage- and Ca2+-dependent K+ (BK) channel is a key element in the control of arterial tone, our aim was to evaluate whether BK channel modulation by tungstate can contribute to its antihypertensive effect.
Dynamic Nature of Atrial Fibrillation Substrate During Development and Reversal of Heart Failure in Dogs
Authors: Kaori Shinagawa, Yan-Fen Shi, Jean-Claude Tardif, Tack-Ki Leung, Stanley Nattel
Journal: Circulation (2002)

Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically.Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs.Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.
Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
Authors: Tzu-Hua Chang, Meng-Feng Tsai, Kang-Yi Su, Shang-Gin Wu, Cheng-Po Huang, Sung-Liang Yu, Yung-Luen Yu, Chou-Chin Lan, Chih-Hsin Yang, Shwu-Bin Lin, Chin-Pyng Wu, Jin-Yuan Shih, Pan-Chyr Yang
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Non–small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown. Objectives: To examine the role of EMT regulators in resistance to gefitinib.Methods: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription–polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription–polymerase chain reaction.Measurements and Main Results: Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells.Conclusions: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.
IL-1R1 is required for dendritic cell–mediated T cell reactivation within the CNS during West Nile virus encephalitis
Authors: Douglas M. Durrant, Michelle L. Robinette, Robyn S. Klein
Journal: The Journal of Experimental Medicine (2013)

Infections of the central nervous system (CNS) with cytopathic viruses require efficient T cell responses to promote viral clearance, limit immunopathology, and enhance survival. We found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the CNS during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1(-/-) mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8(+) T cells. Ex vivo analysis of CD4(+) T cells from WNV-infected CNS of IL-1R1(-/-) mice revealed impaired effector responses, whereas CD8(+) T cells revealed no cell intrinsic defects in response to WNV antigen. WNV-infected, IL-1R1(-/-) mice also exhibited decreased activation of CNS CD11c(+)CD11b(-)CD103(+) and CD11c(+)CD11b(-)CD8α(+)Dec-205(+) cells with reduced up-regulation of the co-stimulatory molecules CD80, CD86, and CD68. Adoptive transfer of wild-type CD11c-EYFP(+) cells from WNV-infected CNS into WNV-infected IL-1R1(-/-) mice trafficked into the CNS restored T cell functions and improved survival from otherwise lethal infection. These data indicate that IL-1R1 signaling promotes virologic control during WNV infection specifically within the CNS via modulation of CD11c(+) cell-mediated T cell reactivation at this site.
A9.6 Effect of mPGES-1 targeting on lipid metabolism in human cells
Authors: Helena Idborg, Joan Raouf, Elena Ossipova, Antonio Checa, Petter Olsson, Patrick Leclerc, Ganna Oliynik, Craig Wheelock, Per-Johan Jakobsson, Marina Korotkova
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme in the induced PGE2 production and well-recognised target for the development of novel anti-inflammatory drugs. Genetic deletion and inhibition of mPGES-1 appears to be protective in experimental models of arthritis. Targeting mPGES-1 alters eicosanoid profiles and may potentially affect the metabolism of other lipids. Fatty acids (FA) play essential roles as energy substrates, membrane structural components, second messengers and precursors of lipid mediators. Genetic deletion of mPGES-1 resulted in reduced levels of MUFA in the spleen suggesting a decreased activity/expression of stearoyl-CoA-desaturase (SCD). SCD has been implicated in modulation of inflammation. However whether mPGES-1 inhibition affects lipid metabolism in human cells is not known. <h3>Objective</h3> To investigate the effect of mPGES-1 deletion/inhibition on lipid metabolism in human cells. <h3>Methods&nbsp;</h3> A549 cells were induced with IL-1b and treated with mPGES-1 inhibitor (compound III) or COX-2 inhibitor (NS398). Eicosanoid profiles were analysed using LC-MS/MS and protein profiles were analysed using mass spectrometry based proteomics. FA composition of total lipids was determined using gas chromatography with flame ionization detector and sphingolipids were analysed by LC-MS/MS. <h3>Results</h3> Proteomic analysis of A549 cells identified the reduction of SCD levels in response to treatment with mPGES-1 or COX-2 inhibitors, as well as the suppression of the levels of a number of proteins involved in metabolism of fatty acids and sphingolipids. <h3>Conclusion</h3> Data reveals that down-regulation of COX-2/mPGES-1/ PGE2 axis affects the lipid metabolism in A549 cells. These effects have important implications regarding potential consequences of pharmacologic mPGES-1 inhibition.