tbuckley/cabot-search huggingface dataset:
Prediction of Incident Diabetic Neuropathy Using the Monofilament Examination
Authors: Bruce A. Perkins, Andrej Orszag, Mylan Ngo, Eduardo Ng, Patti New, Vera Bril
Journal: Diabetes Care (2010)

To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy.Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis.Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6-7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 +/- 2.5 for incident neuropathy vs. 5.7 +/- 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was <or=5 sensate stimuli out of 8, with 72% sensitivity, 64% specificity, positive and negative likelihood ratios of 2.5 and 0.35, and positive and negative predictive values of 87 and 46%, respectively (chi(2) = 20.7, P < 0.001). Area under the ROC curve was significantly greater for the monofilament examination compared with that for other simple sensory tests.A simple threshold of <or=5 sensate stimuli out of 8 discriminates 4-year risk of diabetic neuropathy with acceptable operating characteristics. Although there are limitations in its specificity for prediction of future neuropathy onset, the monofilament examination is appropriate as a simple diabetic neuropathy screening instrument generalizable to the clinical setting.
Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells
Authors: Lilyanne C Grevers, Teun J de Vries, Vincent Everts, J Sjef Verbeek, Wim B van den Berg, Peter L E M van Lent
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To investigate the role of Fcγ receptors (FcγRs) in osteoclastogenesis and osteoclast function. <h3>Methods</h3> Bone destruction was analysed in arthritic knee joints of several FcγR-knockout mouse strains. Unfractionated bone marrow cells were differentiated in vitro towards osteoclasts in the absence or presence of immune complexes (ICs) and stimulated thereafter for 24 h with tumour necrosis factor α (TNFα) or lipopolysaccharide (LPS). In addition, mature osteoclasts were stimulated with ICs. Experiments were analysed for osteoclast formation, bone resorption and the expression of FcγRs and osteoclast markers. <h3>Results</h3> Bone destruction was significantly increased in arthritic knee joints of FcγRIIB-deficient mice. All FcγR classes were highly expressed on osteoclast precursors. Expression of the inhibitory FcγRIIB was similar on mature osteoclasts compared to macrophages, whereas activating FcγR levels were significantly lower. IC stimulation of mature osteoclasts did not affect their number or their bone resorptive capacity. ICs significantly inhibited differentiation of unfractionated bone marrow cells towards osteoclasts, bone resorption and expression of osteoclast markers. In the presence of ICs, osteoclastogenesis of FcγRIIB<sup>−/−</sup> precursors and bone resorption remained inhibited. In contrast, ICs could not inhibit osteoclast formation or bone resorption of FcRγ-chain<sup>−/−</sup> precursors. When IC-inhibited osteoclastogenesis was followed by stimulation with TNFα or LPS, the inhibitory effects of ICs were overruled. <h3>Conclusion</h3> Activating FcγRs mediate IC-induced inhibition of osteoclastogenesis, which might be overruled in the presence of proinflammatory mediators. This suggests that the balance of FcγR-mediated inflammation, through proinflammatory cytokine production, as well as the direct inhibitory effect of ICs on osteoclastogenesis determines the net effect on bone loss.
Is it time to measure lung water by ultrasound?
Authors: Guglielmo M. Trovato, Daniela Catalano, Giuseppe Fabio Martines, Marco Sperandeo
Journal: Intensive Care Medicine (2013)

Dear Editor, The study with 20 patients by Baldi et al. [1] proposes a partially novel application of lung ultrasound in intensive care medicine. They write that ‘‘B-lines are correlated with lung weight and density determined by computed tomography (CT),’’ so that they conclude that ‘‘lung ultrasonography (LUS) may provide a reliable, simple, and radiation-free lung densitometry in the intensive care setting’’ [1]. This conclusion, in our view, is not adequately supported by the present data. Moreover, LUS for lung congestion diagnosis has low predictive power (low sensitivity and specificity), with information that does not discriminate between different conditions [2]: it can be unreliable if not used jointly with thorough clinical assessment. Respiratory function monitoring validated tools have different criteria and features [3]. Actually, the proposed B-lines score has no definite validation through established direct/surrogate lung fluid measurements, and a critical reappraisal is needed. We previously reported, using the different and most currently used criteria, the lack of difference of the number of B-lines in different conditions: heart failure and acute pulmonary edema versus heart failure and pleural effusion and versus pulmonary fibrosis [2]. Did authors challenge their methods in diseases without lung congestion but with many B-line artifacts, such as pulmonary fibrosis [4] and in other conditions [5], finding any significant differences? The regression lines published in the article [1] show an almost perfect relationship of B-line number versus CT-assessed lung density and weight (0.5–2.5 kg). Nonetheless, the weight of the normal adult lung is 0.8–1.2 kg, so we should reasonably imagine that patients have different body dimensions. Are authors measuring a relationship mostly related to body weight as a confounding variable? Moreover, how can the authors be certain that the increase in lung ‘‘weight’’ is due to ‘‘interstitial congestion’’ and not to lung consolidation (atelectasis with pneumonitis, pleural effusion, hemorrhages, and other conditions)? Probably we still need more reliable noninvasive tools for assessing lung water content and its changes. Thank you for your interest and consideration.
Repair of Acute Myocardial Infarction by Human Stemness Factors Induced Pluripotent Stem Cells
Authors: Timothy J. Nelson, Almudena Martinez-Fernandez, Satsuki Yamada, Carmen Perez-Terzic, Yasuhiro Ikeda, Andre Terzic
Journal: Circulation (2009)

Nuclear reprogramming provides an emerging strategy to produce embryo-independent pluripotent stem cells from somatic tissue. Induced pluripotent stem cells (iPS) demonstrate aptitude for de novo cardiac differentiation, yet their potential for heart disease therapy has not been tested.In this study, fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC converted into an embryonic stem cell-like phenotype and demonstrated the ability to spontaneously assimilate into preimplantation host morula via diploid aggregation, unique to bona fide pluripotent cells. In utero, iPS-derived chimera executed differentiation programs to construct normal heart parenchyma patterning. Within infarcted hearts in the adult, intramyocardial delivery of iPS yielded progeny that properly engrafted without disrupting cytoarchitecture in immunocompetent recipients. In contrast to parental nonreparative fibroblasts, iPS treatment restored postischemic contractile performance, ventricular wall thickness, and electric stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue.Fibroblasts reprogrammed by human stemness factors thus acquire the potential to repair acute myocardial infarction, establishing iPS in the treatment of heart disease.
Effects of activation on distribution of Ca2+ in single arterial smooth muscle cells. Determination with fura-2 digital imaging microscopy.
Authors: W F Goldman, W G Wier, M P Blaustein
Journal: Circulation Research (1989)

A rise in cytosolic free Ca2+ is the immediate trigger for contraction in mammalian vascular smooth muscle. We used the fluorescent calcium indicator fura-2 and digital imaging microscopy to study the spatial distribution of intracellular Ca2+ in arterial myocytes and the changes elicited by activation with norepinephrine (NE). Viable arterial myocytes were obtained from bovine tail arteries by enzymatic digestion. In modified Krebs' solution containing 1.8 mM Ca2+, these myocytes were relaxed and spindle-shaped. The cells contracted rapidly when exposed to NE or high-K+ solution ejected from a micropipette; they relaxed slowly when the activator was washed away. NE evoked a rise in Ca2+ concentration ([Ca2+]) in the cells within 100 msec, at a time when the cells had not yet begun to contract. Maximal [Ca2+] levels were attained within 600 msec, at which time the cells were substantially contracted. Digital analysis of images of cellular fura-2 fluorescence revealed that the intracellular [Ca2+] was relatively uniformly distributed prior to activation, with an average resting level of 111 +/- 14 nM (n = 6). During NE-evoked contractions, intracellular [Ca2+] increased, and the distribution of [Ca2+] became much more heterogeneous. On recovery from activation, the cells relaxed, usually attaining less than 90% of their original resting length. In contrast to the relatively uniform Ca2+ distribution observed prior to NE activation, discrete regions of elevated [Ca2+] were observed throughout the recovered cells. The large spatial variation of [Ca2+] after cell activation implies that Ca2+ was sequestered at localized sites in the cell during relaxation.
Physiological responses to the six-minute walk test in older adults
Authors: Victor Dourado, Ricardo Guerra, Letícia Antunes, Suzana Tanni, Irma Godoy
Journal: European Respiratory Journal (2011)

Physiological responses to the six-minute walk test (6MWT) have been increasingly evaluated in patients with cardiopulmonary diseases. However, previous studies did not include healthy persons. The aim of this study was to evaluate age- and gender-related changes in physiological responses to the 6MWT and to establish a set of predictive equations for such variables. We evaluated 102 non-trained healthy older adults (48 men, aged 62±8) stratified in four age groups (40-49; 50-59; 60-69; ≥70). After familiarization, a third 6MWT was performed using a telemetric gas analyzer (k4b2) for assessing metabolic and cardiopulmonary responses as well as oxygen uptake (VO 2 ) time constant (tau) by an exponential fitting. Lean body mass (LBM) (impedance) and handgrip strength (HGS) were measured in 81 subjects. A set of linear equations was provided for prediction of the main physiological variables. The rate of gas exchange (R), VO 2 /heart rate (HR), deficit-O 2  and tauVO 2  were not affected by sex as well as tidal volume (VT), R and VO 2 /HR were not affected by age. Deficit-O 2  and tauVO 2  presented a tendency to age-related changes (p = 0.06). Several prediction equations adjusted by sex, age, height, weight, LBM, HGS, and 6MWT showed R 2  values ranging 0.114 to 0.574 (e.g. deficit-O 2  and VT respectively). The best model for predicting VO 2 peak was adjusted by LBM and age (R 2 =0.435). None of the variables studied was selected as predictive factors for tauVO 2 . Therefore the prediction equations might provide a more appropriate frame of reference for normal physiological responses to the 6MWT in healthy older adults. Our results may be useful for better interpretation of walking performance in patients with cardiopulmonary disease.
Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart
Authors: Byung-Kwan Lim, Dingding Xiong, Andrea Dorner, Tae-Jin Youn, Aaron Yung, Taylor I. Liu, Yusu Gu, Nancy D. Dalton, Adam T. Wright, Sylvia M. Evans, Ju Chen, Kirk L. Peterson, Andrew D. McCulloch, Toshitaka Yajima, Kirk U. Knowlton
Journal: Journal of Clinical Investigation (2008)

The coxsackievirus and adenovirus receptor (CAR) is a transmembrane protein that belongs to the family of adhesion molecules. In the postnatal heart, it is localized predominantly at the intercalated disc, where its function is not known. Here, we demonstrate that a first degree or complete block of atrioventricular (AV) conduction developed in the absence of CAR in the adult mouse heart and that prolongation of AV conduction occurred in the embryonic heart of the global CAR-KO mouse. In the cardiac-specific CAR-KO (CAR-cKO) mouse, we observed the loss of connexin 45 localization to the cell-cell junctions of the AV node but preservation of connexin 40 and 43 in contracting myocardial cells and connexin 30.2 in the AV node. There was also a marked decrease in β-catenin and zonula occludens-1 (ZO-1) localization to the intercalated discs of CAR-cKO mouse hearts at 8 weeks before the mice developed cardiomyopathy at 21 weeks of age. We also found that CAR formed a complex with connexin 45 via its PSD-95/DigA/ZO-1–binding (PDZ-binding) motifs. We conclude that CAR expression is required for normal AV-node conduction and cardiac function. Furthermore, localization of connexin 45 at the AV-node cell-cell junction and of β-catenin and ZO-1 at the ventricular intercalated disc are dependent on CAR.
Relationship of <i>BMPR2</i> Mutations to Vasoreactivity in Pulmonary Arterial Hypertension
Authors: C. Gregory Elliott, Eric W. Glissmeyer, Gregory T. Havlena, John Carlquist, Jason T. McKinney, Stuart Rich, Michael D. McGoon, Mary Beth Scholand, Miryoung Kim, Robert L. Jensen, Jon W. Schmidt, Kenneth Ward
Journal: Circulation (2006)

Background— Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-β type II receptor gene, BMPR2 , predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. Methods and Results— We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations ( P =0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. Conclusions— Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.
Dual effects of phytoestrogens result in u-shaped dose-response curves.
Authors: Kristian Almstrup, Mariana F Fernández, Jørgen H Petersen, Nicolas Olea, Niels E Skakkebaek, Henrik Leffers
Journal: Environmental Health Perspectives (2002)

Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay that simultaneously detects aromatase inhibition and estrogenicity. The principle is similar to that of other MCF-7 estrogenicity assays, but with a fixed amount of testosterone added. The endogenous aromatase activity in MCF-7 cells converts some of the testosterone to 17beta-estradiol, which is assayed by quantifying differences in the expression level of the estrogen-induced pS2 mRNA. Potential aromatase inhibitors can be identified by a dose-dependent reduction in the pS2 mRNA expression level after exposure to testosterone and the test compound. Using this assay, we have investigated several compounds, including synthetic chemicals and phytoestrogens, for aromatase inhibition. The phytoestrogens, except genistein, were aromatase inhibitors at low concentrations (< 1 micro M) but estrogenic at higher concentrations (greater than or equal to 1 micro M), resulting in U-shaped dose-response curves. None of the tested synthetic chemicals were aromatase inhibitors. The low-dose aromatase inhibition distinguished phytoestrogens from other estrogenic compounds and may partly explain reports about antiestrogenic properties of phytoestrogens. Aromatase inhibition may play an important role in the protective effects of phytoestrogens against breast cancer.
Use and Outcomes of Adjuvant Chemotherapy in Older Women With Breast Cancer
Authors: Sharon H. Giordano, Zhigang Duan, Yong-Fang Kuo, Gabriel N. Hortobagyi, James S. Goodwin
Journal: Journal of Clinical Oncology (2006)

Purpose This study was undertaken to determine patterns and outcomes of adjuvant chemotherapy use in a population-based cohort of older women with primary breast cancer. Patients and Methods Women were identified from the Surveillance, Epidemiology, and End Results–Medicare-linked database who met the following criteria: age ≥ 65 years, stage I to III breast cancer, and diagnosis between 1991 and 1999. Adjuvant chemotherapy use was ascertained by Common Procedural Terminology J codes. Logistic regression analysis was performed to determine factors associated with chemotherapy use. Multivariate Cox proportional hazards models were used to calculate the hazard of death for women with and without chemotherapy. Results A total of 41,390 women met study criteria, of whom 4,500 (10.9%) received chemotherapy. The use of adjuvant chemotherapy more than doubled during the 1990s, from 7.4% in 1991 to 16.3% in 1999 (P &lt; .0001), with a significant shift toward anthracycline use. Women who were younger, white, with lower comorbidity scores, more advanced stage disease, and estrogen receptor (ER) –negative disease were significantly more likely to receive chemotherapy. Chemotherapy was not associated with improved survival among women with lymph node–negative (LN) disease or LN-positive, ER-positive disease (hazard ratio [HR], 1.05; 95% CI, 0.85 to 1.31). However, among women with LN-positive, ER-negative breast cancer, chemotherapy was associated with a significant reduction in breast cancer mortality (HR, 0.72; 95% CI, 0.54 to 0.96). A similar significant benefit of chemotherapy was seen in the subset of women age 70 years or older (HR, 0.74; 95% CI, 0.56 to 0.97). Conclusion In this observational cohort, chemotherapy was associated with a significant reduction in mortality among older women with ER-negative, LN-positive breast cancer.
Use of silicone stents for the management of post-tuberculosis tracheobronchial stenosis
Authors: Y. J. Ryu, H. Kim, C. M. Yu, J. C. Choi, Y. S. Kwon, O. J. Kwon
Journal: European Respiratory Journal (2006)

The role of bronchoscopic management in post-tuberculosis tracheobronchial stenosis is not well defined. To investigate the role of bronchoscopic intervention, including silicone stenting, in the management of post-tuberculosis tracheobronchial stenosis, the current retrospective study was conducted at a tertiary referral hospital. Under rigid bronchoscopy, 80 patients underwent ballooning, neodymium-yttrium aluminium garnet laser resection and/or bougienation as first-line methods of airway dilatation between January 2000 and December 2003 inclusive, and were followed for a median of 41 months. Silicone stents were required in 75 out of 80 (94%) patients to maintain airway patency. Bronchoscopic intervention provided immediate symptomatic relief and improved lung function in 88% of the patients. After airway stabilisation, stents were removed successfully in 49 out of 75 (65%) patients at a median of 14 months post-insertion. Three patients out of 75 (4%) eventually underwent surgical management. Acute complications included: excessive bleeding (n = 1); pneumothorax (n = 5); and pneumomediastinum without mortality (n = 2). Stent-related late complications, such as migration (51%), granuloma formation (49%), mucostasis (19%) and re-stenosis (40%), were controllable during a median follow-up of 41 months. In conclusion, bronchoscopic intervention, including silicone stenting, could be a useful and safe method for treating post-tuberculosis tracheobronchial stenosis.
Observations on the Regulation of Arterial Blood Pressure in Unanesthetized Dogs
Authors: JOHN J. LAMBERTI, JOHN URQUHART, RALPH D. SIEWERS, Charles Pearson
Journal: Circulation Research (1968)

Aortic pressure rises as a dog's head is raised and falls as it is lowered. Systemic pressure change was 49%±3% of the hydrostatic pressure change at the carotid sinus, chosen as an arbitary reference, so that pressure at the carotid sinus changed only 51% as much as it would have if systemic pressure had not changed. The responses to head raising and lowering were dynamically asymmetrical, in a way which permits them to be described as being dependent on the rate of head lowering as well as on vertical position. When chloralose-anesthetized dogs maintained with positive-pressure breathing were studied under water, the response was abolished, suggesting its hydrostatic basis. Chronic carotid baroreceptor deafferentation or carotid sinus excision only diminished the response to changes in head position in most animals, and a transient response to head lowering persisted in all. An apparent CNS adaptation to the disruption of baroreceptor afferents makes it impossible to judge the quantitative role of the carotid sinus reflex in the relation of head position to blood pressure in intact dogs. The effect of head motion on blood pressure are predictable in a model of blood pressure control basedon the known dynamic relations between carotid sinus and systemic pressures, from which we tentatively conclude that vertical head motion acts on blood pressure through the carotid sinus reflex. If so, the measurement of vascular responses to head motion can serve as a nondestructive, quantitative test of baroreceptor reflex dynamics in intact, unanesthetized animals.