tbuckley/cabot-search huggingface dataset:
Statistical and Substantive Inferences in Public Health: Issues in the Application of Multilevel Models
Authors: Jeffrey B. Bingenheimer, Stephen W. Raudenbush
Journal: Annual Review of Public Health (2004)

Multilevel statistical models have become increasingly popular among public health researchers over the past decade. Yet the enthusiasm with which these models are being adopted may obscure rather than solve some problems of statistical and substantive inference. We discuss the three most common applications of multilevel models in public health: (a) cluster-randomized trials, (b) observational studies of the multilevel etiology of health and disease, and (c) assessments of health care provider performance. In each area of investigation, we describe how multilevel models are being applied, comment on the validity of the statistical and substantive inferences being drawn, and suggest ways in which the strengths of multilevel models might be more fully exploited. We conclude with a call for more careful thinking about multilevel causal inference.
Magnetic Resonance Imaging Response Monitoring of Breast Cancer During Neoadjuvant Chemotherapy: Relevance of Breast Cancer Subtype
Authors: Claudette E. Loo, Marieke E. Straver, Sjoerd Rodenhuis, Sara H. Muller, Jelle Wesseling, Marie-Jeanne T.F.D. Vrancken Peeters, Kenneth G.A. Gilhuijs
Journal: Journal of Clinical Oncology (2011)

Purpose To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC). Patients and Methods MRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations. Results Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P &lt; .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearson's r = 0.465; P &lt; .001). In subset analysis, this was only significant for triple-negative tumors (P &lt; .001) and HER2-positive tumors (P &lt; .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P &lt; .001). No associations were found for ER-positive/HER2-negative tumors. Conclusion MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.
Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells
Authors: Julie Hanson Ostrander, Andrea R. Daniel, Kristopher Lofgren, Celina G. Kleer, Carol A. Lange
Journal: Cancer Research (2007)

Abstract Total tyrosine kinase activity is often elevated in both cytosolic and membrane fractions of malignant breast tissue and correlates with a decrease in disease-free survival. Breast tumor kinase (Brk; protein tyrosine kinase 6) is a soluble tyrosine kinase that was cloned from a metastatic breast tumor and found to be overexpressed in a majority of breast tumors. Herein, we show that Brk is overexpressed in 86% of invasive ductal breast tumors and coexpressed with ErbB family members in breast cancer cell lines. Additionally, the ErbB ligand, heregulin, activates Brk kinase activity. Knockdown of Brk by stable expression of short hairpin RNA (shRNA) in T47D breast cancer cells decreases proliferation and blocks epidermal growth factor (EGF)- and heregulin-induced activation of Rac GTPase, extracellular signal-regulated kinase (ERK) 5, and p38 mitogen-activated protein kinase (MAPK) but not Akt, ERK1/2, or c-Jun NH2-terminal kinase. Furthermore, EGF- and heregulin-induced cyclin D1 expression is dependent on p38 signaling and inhibited by Brk shRNA knockdown. The myocyte enhancer factor 2 transcription factor target of p38 MAPK and ERK5 signaling is also sensitive to altered Brk expression. Finally, heregulin-induced migration of T47D cells requires p38 MAPK activity and is blocked by Brk knockdown. These results place Brk in a novel signaling pathway downstream of ErbB receptors and upstream of Rac, p38 MAPK, and ERK5 and establish the ErbB-Brk-Rac-p38 MAPK pathway as a critical mediator of breast cancer cell migration. [Cancer Res 2007;67(9):4199–209]
Incidence of Aortic Complications in Patients With Bicuspid Aortic Valves
Authors: Hector I Michelena, Amber D Khanna, Douglas Mahoney, Edit Margaryan, Yan Topilsky, Rakesh M Suri, Ben Eidem, William D Edwards, Thoralf M Sundt, Maurice Enriquez-Sarano
Journal: JAMA (2011)

Bicuspid aortic valve (BAV), the most common congenital heart defect, has been thought to cause frequent and severe aortic complications; however, long-term, population-based data are lacking.To determine the incidence of aortic complications in patients with BAV in a community cohort and in the general population.In this retrospective cohort study, we conducted comprehensive assessment of aortic complications of patients with BAV living in a population-based setting in Olmsted County, Minnesota. We analyzed long-term follow-up of a cohort of all Olmsted County residents diagnosed with definite BAV by echocardiography from 1980 to 1999 and searched for aortic complications of patients whose bicuspid valves had gone undiagnosed. The last year of follow-up was 2008-2009.Thoracic aortic dissection, ascending aortic aneurysm, and aortic surgery.The cohort included 416 consecutive patients with definite BAV diagnosed by echocardiography, mean (SD) follow-up of 16 (7) years (6530 patient-years). Aortic dissection occurred in 2 of 416 patients; incidence of 3.1 (95% CI, 0.5-9.5) cases per 10,000 patient-years, age-adjusted relative-risk 8.4 (95% CI, 2.1-33.5; P = .003) compared with the county's general population. Aortic dissection incidences for patients 50 years or older at baseline and bearers of aortic aneurysms at baseline were 17.4 (95% CI, 2.9-53.6) and 44.9 (95% CI, 7.5-138.5) cases per 10,000 patient-years, respectively. Comprehensive search for aortic dissections in undiagnosed bicuspid valves revealed 2 additional patients, allowing estimation of aortic dissection incidence in bicuspid valve patients irrespective of diagnosis status (1.5; 95% CI, 0.4-3.8 cases per 10,000 patient-years), which was similar to the diagnosed cohort. Of 384 patients without baseline aneurysms, 49 developed aneurysms at follow-up, incidence of 84.9 (95% CI, 63.3-110.9) cases per 10,000 patient-years and an age-adjusted relative risk 86.2 (95% CI, 65.1-114; P <.001 compared with the general population). The 25-year rate of aortic surgery was 25% (95% CI, 17.2%-32.8%).In the population of patients with BAV, the incidence of aortic dissection over a mean of 16 years of follow-up was low but significantly higher than in the general population.
Transcriptional activation of RACTK1 K+ channel gene by apical alkalization in renal cortical collecting duct cells.
Authors: M Ikeda, M Murata, T Miyoshi, K Tamba, S Muto, M Imai, M Suzuki
Journal: Journal of Clinical Investigation (1996)

We have previously demonstrated that RACTK1 cDNA encodes a pH sensitive K+ channel expressed in the apical side of renal collecting tubule cells. To determine whether extracellular pH induces the RACTK1 gene expression in the renal cortical collecting duct (CCD) cells, we measured mRNA of the RACTK1 using cultured rabbit CCD cells. Alkalization of incubation medium activated the transcription of the RACKTK1 gene in a time- and dose-dependent manner after 1 h, and reached a maximal level after 12 h. To examine whether the stimulation of mRNA by alkalization of body fluid occurs also in vivo, mRNA levels were measured in mice loaded with acid or alkali. The RACTK1 mRNA was increased in association with the rise in urinary pH. To examine side face of the effect of pH on stimulation of mRNA, we observed the effect of pH in the apical or the basolateral side in the preparation where CCD cells were cultured on filter membrane supports. Alkalization of the apical side but not of the basolateral side, was shown to be a determinant in inducting the RACTK1 mRNA. These findings suggest that, in addition to rapid direct regulation of RACTK1 K+ channel conductance by intracellular pH, this channel is also regulated by the changes in luminal pH through synthesis of channel protein by transcriptional activation.
Dynamic respiratory mechanics and exertional dyspnoea in pulmonary arterial hypertension
Authors: Pierantonio Laveneziana, Gilles Garcia, Barbara Joureau, Fadia Nicolas-Jilwan, Toufik Brahimi, Louis Laviolette, Olivier Sitbon, Gérald Simonneau, Marc Humbert, Thomas Similowski
Journal: European Respiratory Journal (2012)

Patients with pulmonary arterial hypertension (PAH) may exhibit reduced expiratory flows at low lung volumes, which could promote exercise-induced dynamic hyperinflation (DH). This study aimed to examine the impact of a potential exercise-related DH on the intensity of dyspnoea in patients with PAH undergoing symptom-limited incremental cardiopulmonary cycle exercise testing (CPET). 25 young (aged mean± sd 38±12 yrs) nonsmoking PAH patients with no evidence of spirometric obstruction and 10 age-matched nonsmoking healthy subjects performed CPET to the limit of tolerance. Ventilatory pattern, operating lung volumes (derived from inspiratory capacity (IC) measurements) and dyspnoea intensity (Borg scale) were assessed throughout CPET. IC decreased ( i.e. DH) progressively throughout CPET in PAH patients (average 0.15 L), whereas it increased in all the healthy subjects (0.45 L). Among PAH patients, 15 (60%) exhibited a decrease in IC throughout exercise (average 0.50 L), whereas in the remaining 10 (40%) patients IC increased (average 0.36 L). Dyspnoea intensity and ventilation were greater in PAH patients than in controls at any stage of CPET, whereas inspiratory reserve volume was lower. We conclude that DH-induced mechanical constraints and excessive ventilatory demand occurred in these young nonsmoking PAH patients with no spirometric obstruction and was associated with exertional dyspnoea.
Identification and Characterization of a T-Helper Peptide from Carcinoembryonic Antigen
Authors: Marta Ruiz, Hiroya Kobayashi, Juan José Lasarte, Jesús Prieto, Francisco Borrás-Cuesta, Esteban Celis, Pablo Sarobe
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to identify promiscuous T-helper cell determinants (THd) from carcinoembryonic antigen (CEA) to be used to prime T-cell help for cancer therapy. CEA was selected because this antigen is expressed in an important variety of carcinomas. Experimental Design: Potential promiscuous THd from CEA were predicted using available computer algorithms. Predicted peptides were synthesized and tested in binding experiments to different HLA-DR molecules. Binder peptides were then used to prime T-cell responses both in vitro and in vivo. Results: Twenty 15-mer peptides from CEA were predicted to bind to different HLA-DR molecules. The promiscuous character of these peptides was demonstrated in binding experiments. Fifteen of 20 peptides tested were able to bind to HLA-DR4, but only CEA (625–639) was shown to be presented after processing of recombinant CEA. CEA (625–639) was also found to be presented by HLA-DR53. Moreover, immunization of HLA-DR4 transgenic mice with CEA (625–639) in conjunction with class I epitope OVA (257–264), induced a CTL response specific of OVA (257–264). Conclusions: CEA (625–639) might be a relevant promiscuous THd peptide for cancer therapy.
Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Metastases
Authors: Kyle E. Rusthoven, Brian D. Kavanagh, Stuart H. Burri, Changhu Chen, Higinia Cardenes, Mark A. Chidel, Thomas J. Pugh, Madeleine Kane, Laurie E. Gaspar, Tracey E. Schefter
Journal: Journal of Clinical Oncology (2009)

To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three lung metastases. Patients with one to three lung metastases with cumulative maximum tumor diameter smaller than 7 cm were enrolled and treated on a multi-institutional phase I/II clinical trial in which they received SBRT delivered in 3 fractions. In phase I, the total dose was safely escalated from 48 to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points included toxicity and survival. Thirty-eight patients with 63 lesions were enrolled and treated at three participating institutions. Seventy-one percent had received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, zero to five). Two patients had local recurrence after prior surgical resection. There was no grade 4 toxicity. The incidence of any grade 3 toxicity was 8% (three of 38). Symptomatic pneumonitis occurred in one patient (2.6%). Fifty lesions were assessable for local control. Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Actuarial local control at one and two years after SBRT was 100% and 96%, respectively. Local progression occurred in one patient, 13 months after SBRT. Median survival was 19 months. This multi-institutional phase I/II trial demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.
The Dominance of Scientific English
Authors: David Robertson
Journal: JAMA (1983)

THE DISSEMINATION and ascendancy of the English language is surely one of the most remarkable events of modern times.<sup>1</sup>As recently as the year 1500, the language was restricted to a modest portion of the island of Britain and claimed no more than 5 million speakers.<sup>2</sup>There were larger numbers of people speaking French, German, Russian, Chinese, Japanese, Spanish, Italian, Hindi-Urdu, Quechua (Inca), and perhaps other tongues. There was certainly no reason then to have anticipated the bright future of English as a language of wider communication. Indeed, at that time, French was rapidly becoming established as the language of culture and diplomacy. The extent to which French was to develop as an international language is illustrated by the 1814-1815 Congress of Vienna, where the victorious nations conducted all proceedings in French, the language of the defeated country. It was only in the 19th century with the worldwide
STUDIES IN MAN OF THE VOLUME OF THE RESPIRATORY DEAD SPACE AND THE COMPOSITION OF THE ALVEOLAR GAS 1
Authors: A. P. Fishman
Journal: Journal of Clinical Investigation (1954)

Interest is currently focussed on the analysis of the factors influencing the exchange of oxygen and carbon dioxide between the blo)10 an(l gas phases of the lung under a variety of experimental condi- tions. To this end, respirator)' equations have been developed which inclutde as unkinowins either the volume of the respiratory dead space or the composition of alveolar gas. A new indirect method for determination of these two essential factors has been recently described by Pappen- heimer, Fishman, and Borrero (1) and studied in anesthetized dogs and also in a few normal sub- jects. This method, hereafter referred to as the iso-saturation method. makes possible the graphic solution of the Bohr formiiula for both the volume of the respiratory deadl space and for the composition of alveolar gas; it entails the mleas- urement of the composition of expired air over a wide range of tidal volumes, while respiratory gas tensions in the blood leaving the lungs are main- tained constant during controlled hypoxemia. The purpose of this paper is to extend the ob- servations made on normal man with the iso-satu- ration method, and to explore its applicability to subjects with abnormal pulmonary functioni.
Ecto-5′ Nucleotidase (CD73)-Mediated Adenosine Generation and Signaling in Murine Cardiac Allograft Vasculopathy
Authors: Tomomi Hasegawa, Diane Bouïs, Hui Liao, Scott H. Visovatti, David J. Pinsky
Journal: Circulation Research (2008)

Ecto-5′-nucleotidase (CD73) catalyzes the terminal phosphohydrolysis of 5′-adenosine monophosphate and is widely expressed on endothelial cells where it regulates barrier function. Because it is also expressed on lymphocytes, we hypothesized that it modulates vascular immune regulation under homeostatic conditions and dysregulation under stress conditions such as cardiac allotransplantation. In a heterotopic cardiac allotransplantation model, CD73 deficiency in either donors or recipients resulted in decreased graft survival and the development of cardiac allograft vasculopathy, suggesting a contribution of CD73 on both graft-resident and circulating cells in vasculopathy pathogenesis. Vascular perturbations incited by lack of CD73 included loss of graft barrier function and diminished graft expression of the A 2B adenosine receptor (A 2B AR), with a concordant exacerbation of the acute inflammatory and immune responses. The importance of CD73 in modulating endothelial–lymphocyte interaction was further demonstrated in allomismatched in vitro coculture experiments. Either genetic deletion or pharmacological blockade of CD73 increased transendothelial lymphocyte migration and inflammatory responses, suggesting that CD73 plays a critical role to suppress transendothelial leukocyte trafficking through its enzymatic activity. In addition, antagonism of A 2B AR caused a significant increase in vascular leakage, and agonism of A 2B AR resulted in marked prolongation of graft survival and suppression of cardiac allograft vasculopathy development. These data suggest a new paradigm in which phosphohydrolysis of adenosine monophosphate by CD73 on graft-resident or circulating cells diminishes transendothelial leukocyte trafficking and mitigates inflammatory and immune sequelae of cardiac transplantation via the A 2B AR.
Pervasive Indels and Their Evolutionary Dynamics after the Fish-Specific Genome Duplication
Authors: Baocheng Guo, Ming Zou, Andreas Wagner
Journal: Molecular Biology and Evolution (2012)

Insertions and deletions (indels) in protein-coding genes are important sources of genetic variation. Their role in creating new proteins may be especially important after gene duplication. However, little is known about how indels affect the divergence of duplicate genes. We here study thousands of duplicate genes in five fish (teleost) species with completely sequenced genomes. The ancestor of these species has been subject to a fish-specific genome duplication (FSGD) event that occurred approximately 350 Ma. We find that duplicate genes contain at least 25% more indels than single-copy genes. These indels accumulated preferentially in the first 40 my after the FSGD. A lack of widespread asymmetric indel accumulation indicates that both members of a duplicate gene pair typically experience relaxed selection. Strikingly, we observe a 30–80% excess of deletions over insertions that is consistent for indels of various lengths and across the five genomes. We also find that indels preferentially accumulate inside loop regions of protein secondary structure and in regions where amino acids are exposed to solvent. We show that duplicate genes with high indel density also show high DNA sequence divergence. Indel density, but not amino acid divergence, can explain a large proportion of the tertiary structure divergence between proteins encoded by duplicate genes. Our observations are consistent across all five fish species. Taken together, they suggest a general pattern of duplicate gene evolution in which indels are important driving forces of evolutionary change.
How to avoid precipitating an acute adrenal crisis
Authors: J. A. H. Wass, W. Arlt
Journal: BMJ (2012)

Most importantly, heed patients’ requests for hydrocortisone 

There are two hormone deficiency syndromes that are rapidly fatal if untreated but which are quite easily managed. One is type 1 diabetes mellitus, commonly known to be treatable with insulin. The other is acute adrenocortical insufficiency (adrenal or so called addisonian crisis), which requires treatment with hydrocortisone. Unfortunately, too often, healthcare workers do not realise the urgency of treatment for acute adrenal crisis or fail to heed the requests of well informed patients for hydrocortisone.

Patients with adrenal insufficiency are at risk of developing life threatening adrenal crisis if steroids are reduced or stopped, or if glucocorticoid treatment is not increased during periods of increased stress (for example, illness, trauma, or surgery). The features of acute adrenal crisis include hypotension (particularly postural hypotension), shock, and hyponatraemia in 90% of patients. Hyperkalaemia is also a feature in 65% of patients. Fatal but avoidable addisonian crisis is the second most common cause of death in patients with known Addison’s disease, accounting for 15% of deaths in patients with this disease.1 2 Early treatment with parenteral hydrocortisone and intravenous rehydration with fluids are essential measures to avoid mortality. Why is this not always achieved?

The Addison’s Disease Self Help Group (www.addisons.org.uk/), a charity that informs and supports patients with Addison’s disease, has …