tbuckley/cabot-search huggingface dataset:
Microvascular Responses to Alterations in Oxygen Tension
Authors: Brian R. Duling
Journal: Circulation Research (1972)

The changes in microvascular diameter and perivascular oxygen tension resulting from alterations in suffusion solution Po 2 were investigated in a study of the participation of oxygen in the regulation of blood flow. Diffusion gradients for oxygen were altered by changing the Po 2 of a solution covering the surface of the hamster cheek pouch. As the solution Po 2 was raised from a low of 11 mm Hg, perivascular Po 2 of the large arterioles initially decreased to a minimum at approximately 40 mm Hg and then increased progressively as solution Po 2 was elevated further. Arterial capillary and tissue Po 2 remained relatively constant over a range of solution oxygen tensions between 11 and 40 mm Hg, suggesting that either the precapillary sphincters or the terminal arterioles were active in regulating tissue Po 2 as the input of O 2 from the solution was increased. The arterioles constricted as solution Po 2 was elevated. Average arteriolar diameter decreased by 13% as solution Po 2 increased from 11 to 47 mm Hg. A more pronounced constriction of 20% occurred when solution Po 2 was increased from 11 to 84 mm Hg. These experiments indicated that the response of large and small arterioles was not mediated by a direct effect of oxygen on the vascular smooth muscle, since decreases in perivascular oxygen tension were coincident with decreases in vascular diameter in these vessels over a range of solution Po 2 between 11 and 47 mm Hg. The data did not distinguish between a direct and an indirect effect of oxygen on the vascular smooth muscle of the terminal arterioles and precapillary sphincters. However, the oxygen tensions measured at these sites (18-30 mm Hg) required that the vascular smooth muscle cells respond to altered oxygen tension at levels higher than those which have been demonstrated experimentally.
Abatacept or tocilizumab after rituximab in rheumatoid arthritis? An exploratory study suggests non-response to rituximab is associated with persistently high IL-6 and better clinical response to IL-6 blocking therapy
Authors: Sudipto Das, Edward M Vital, Sarah Horton, Domini Bryer, Yasser El-Sherbiny, Andrew C Rawstron, Frederique Ponchel, Paul Emery, Maya H Buch
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To evaluate the efficacy and safety of two different targeted approaches—abatacept or tocilizumab—after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy. <h3>Methods</h3> Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR. <h3>Results</h3> In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p&lt;0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237). <h3>Conclusion</h3> In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.
Early Expression of Myocardial HIF-1α in Response to Mechanical Stresses
Authors: Chan-Hyung Kim, Young-Suk Cho, Yang-Sook Chun, Jong-Wan Park, Myung-Suk Kim
Journal: Circulation Research (2002)

Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1alpha subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts. In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1alpha accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was found to be activated by mechanical stress and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction of HIF-1alpha and VEGF was suppressed by gadolinium (a stretch-activated channel inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest that HIF-1alpha plays an important role in the induction of VEGF in nonischemic and mechanically stressed myocardium, and that this is regulated by stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this signaling pathway, which induces HIF-1alpha, seems to play an important role in the adaptation of the myocardium to stresses. The full text of this article is available at http://www.circresaha.org.
Differentiation of Human Embryonal Carcinomas <i>In vitro</i> and <i>In vivo</i> Reveals Expression Profiles Relevant to Normal Development
Authors: Rolf I. Skotheim, Guro E. Lind, Outi Monni, Jahn M. Nesland, Vera M. Abeler, Sophie D. Fosså, Nur Duale, Gunnar Brunborg, Olli Kallioniemi, Peter W. Andrews, Ragnhild A. Lothe
Journal: Cancer Research (2005)

Abstract Embryonal carcinoma is a histologic subgroup of testicular germ cell tumors (TGCTs), and its cells may follow differentiation lineages in a manner similar to early embryogenesis. To acquire new knowledge about the transcriptional programs operating in this tumor development model, we used 22k oligo DNA microarrays to analyze normal and neoplastic tissue samples from human testis. Additionally, retinoic acid–induced in vitro differentiation was studied in relevant cell lines. We identified genes characterizing each of the known histologic subtypes, adding up to a total set of 687 differentially expressed genes. Among these, there was a significant overrepresentation of gene categories, such as genomic imprinting and gene transcripts associated to embryonic stem cells. Selection for genes highly expressed in the undifferentiated embryonal carcinomas resulted in the identification of 58 genes, including pluripotency markers, such as the homeobox genes NANOG and POU5F1 (OCT3/4), as well as GAL, DPPA4, and NALP7. Interestingly, abundant expression of several of the pluripotency genes was also detected in precursor lesions and seminomas. By use of tissue microarrays containing 510 clinical testicular samples, GAL and POU5F1 were up-regulated in TGCT also at the protein level and hence validated as diagnostic markers for undifferentiated tumor cells. The present study shows the unique gene expression profiles of each histologic subtype of TGCT from which we have identified deregulated components in selected processes operating in normal development, such as WNT signaling and DNA methylation.
Privacy in Psychiatric Treatment: Threats and Responses
Authors: Paul S. Appelbaum
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The author provides an overview of the current status of privacy in psychiatric treatment, with particular attention to the effects of new federal regulations authorized by the Health Insurance Portability and Accountability Act (HIPAA). METHOD: The author reviews the ethical and legal underpinnings for medical privacy, including the empirical data supporting its importance; discusses those portions of the new federal regulations most relevant to psychiatric practice; and suggests steps that psychiatrists can take to maintain their patients’ privacy in the new environment. RESULTS: Medical ethics and law, in keeping with patients’ preferences, traditionally have provided strong protection for the information that patients communicate while receiving medical care. In general, release of information has required patients’ explicit consent. However, limitations of the consent model and technological innovations that permit the aggregation of computerized medical information have led to pressure for greater access to these data. Although the new federal regulations offer patients some additional protections (including security for psychotherapy notes), they also mark a retreat from reliance on patient consent and open up records to previously unauthorized uses, among them law enforcement investigations and marketing and fundraising by health care organizations. However, states retain the power to provide higher levels of protection. CONCLUSIONS: The new regulatory environment is less friendly to medical privacy but still leaves a great deal of discretion in physicians’ hands. A commitment to protecting privacy as an ethical norm can be advanced by psychiatrists’ requesting patients’ consent even when it is not required, by ensuring that patients are aware of the limits on confidentiality, and by avoiding unnecessary breaches of privacy in the course of providing psychiatric care.
Diffuse Mesothelin Expression Correlates with Prolonged Patient Survival in Ovarian Serous Carcinoma
Authors: M. Jim Yen, Chih-Yi Hsu, Tsui-Lien Mao, T-C. Wu, Richard Roden, Tian-Li Wang, Ie-Ming Shih
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Mesothelin is an emerging marker for cancer diagnosis and target-based therapy, yet relatively little is known about the clinical significance of mesothelin expression in tumors. In this study, we correlate mesothelin immunoreactivity to clinicopathologic features in ovarian serous carcinoma. Experimental Design: Mesothelin expression levels were compared among 81 publicly available serial analysis of gene expression (SAGE) libraries of various carcinoma and normal tissue types. Immunohistochemistry using a well-characterized mesothelin monoclonal antibody (5B2) was done to evaluate mesothelin expression in 167 high-grade and 31 low-grade ovarian serous carcinomas. Immunohistochemistry staining scores were correlated with patient survival, tumor site, tumor grade, in vitro drug resistance, and differentiation status of tumor cells. Results: SAGE analysis showed that mesothelin was overexpressed in 50% of ovarian and pancreatic carcinomas but rarely in other cancer types, including liver, colon, kidney, prostate, and breast. Mesothelin immunoreactivity (&amp;gt;5% of tumor cells) was present in 55% of ovarian serous carcinomas with no difference in expression between high-grade and low-grade serous tumors (P = 0.82). Based on Kaplan-Meier analysis, we found that a diffuse mesothelin staining (&amp;gt;50% of tumor cells) in primary high-grade ovarian carcinomas correlated significantly with prolonged survival in patients who had advanced-stage disease and had received optimal debulking surgery followed by chemotherapy (P = 0.023). Mesothelin expression did not correlate significantly with patient age, tumor site, in vitro drug resistance, or tumor differentiation status (P &amp;gt; 0.10). Conclusion: Our results provided new evidence that mesothelin expression is associated with prolonged survival in patients with high-grade ovarian serous carcinoma.
Endoscopic Mucosectomy Using an Esophageal Variceal Ligation Device for Minute Gastric Cancer
Authors: D. K. Lee, S. W. Lee, S. O. Kwon, W. I. Jang, Y. H. Shim, M. Y. Cho
Journal: Endoscopy (1996)

We present here a modified technique for endoscopic mucosal resection using the technique of esophageal variceal ligation for minute gastric cancer. This method of endoscopic mucosal resection requires only the commonly-used one-channel endoscope, an esophageal variceal ligation device, and some clinical experience with the ligation of esophageal varices and snare polypectomy. It can therefore be considered technically simple and safe. We treated four patients with minute gastric cancer using this endoscopic mucosal resection technique. All tumors were completely resected without major complications. Resected specimens were 1.0-1.5 cm in diameter, sufficient for histopathological evaluation, and curative resection was achieved in all patients.
Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than Triple-Negative Phenotype
Authors: Maggie C.U. Cheang, David Voduc, Chris Bajdik, Samuel Leung, Steven McKinney, Stephen K. Chia, Charles M. Perou, Torsten O. Nielsen
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. Experimental Design: Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels. Results: Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. Conclusions: The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.
Is Dowling—Degos disease the same disease as Kitamura's reticulate acropigmentation?
Authors: F. CROVATO, G. DESIRELLO, A. REBORA
Journal: British Journal of Dermatology (1983)

A patient is described with the clinical and histopathological features of both Dowling–Degos disease and Kitamura's acropigmentatio reticularis. The possible identity of the two genodermatoses is discussed on the basis of the similarity of their clinical and histopathological features and of the presence of the two diseases in the family of the propositus.
Rehabilitation after anterior cruciate ligament injury influences joint loading during walking but not hopping
Authors: M A Risberg, H Moksnes, A Storevold, I Holm, L Snyder-Mackler
Journal: British Journal of Sports Medicine (2009)

The purpose of this study was to identify changes in clinical outcome and lower extremity biomechanics during walking and hopping in ACL-injured subjects before and after a 20-session neuromuscular and strength training programme.Pre and post experimental design.Outpatient clinic, primary care.32 subjects with unilateral ACL injury, mean 60 (SD 35) days after injury, with a mean age of 26.2 (5.4) years.The rehabilitation programme consisted of neuromuscular and strength exercises.Outcome measurements assessed before and after a 20-session rehabilitation programme were: self-assessment questionnaires (KOS-ADL, IKDC2000, Global function), four single-leg hop tests, and isokinetic muscle strength tests. Lower extremity kinematics and kinetics were captured during the stance phase of gait and landing after a single leg hop, synchronised with three force plates.These ACL-injured individuals significantly improved their clinical outcome after rehabilitation. Gait analysis disclosed a significantly improved knee extension moment after rehabilitation, but no change in hip or knee excursions. During landing after hop no change in knee excursion or knee moment was recorded.After rehabilitation the ACL-injured subjects showed a significantly improved clinical outcome, but lower extremity biomechanics were still significantly impaired during both walking and hopping. The rehabilitation programme influenced knee joint loading during walking, but not during hopping. Longer rehabilitation should be considered before ACL-injured individuals return to jumping activities.
Deficient elevation of the cytoplasmic calcium ion concentration by epinephrine in epinephrine‐insensitive platelets of patients with myeloproliferative disorders
Authors: Fumitaka Ushikubi, Minoru Okuma, Takafumi Ishibashi, Shuh Narumlya, Haruto Uchino
Journal: American Journal of Hematology (1990)

Abstract Elevation of the cytoplasmic Ca 2+ concentration ([Ca 2 + ]i) by epinephrine and epinephrine‐induced inhibition of prostaglandin E 1 (PGE 1 )‐stimulated cyclic adenosine monophosphate (CAMP) accumulation were assessed in platelets from three groups of subjects: normal controls (NS, n = 11) and patients with myeloproliferative disorders whose platelets were either sensitive (ES, n = 9) or specifically insensitive (El, n = 7) to the aggregatory effect of epinephrine. The inhibition by epinephrine of CAMP accumulation in the platelets exposed to 500 nM PGE, was not significantly different between the three groups. Therefore, despite the detective aggregation response to epinephrine, platelets from the El group seemed to retain normal response, which was attained through cα 2 ‐adrenergic receptors, guanine nucleotide binding regulatory protein, and the adenylate cyclase system. However, in aequorin‐loaded, washed platelets, the epinephrine‐stimu‐lated rise in [Ca 2+ ]i showed significant decrease in the El group compared with the other groups (P &lt; 0.01). Thus the mechanism for the impaired aggregation response to epinephrine in platelets from the El group could include the defect that exists in the pathway from receptor binding of epinephrine to the aggregation response through [Ca 2+ ]i elevation.
Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis
Authors: Francesco Villa, Albino Carrizzo, Chiara C. Spinelli, Anna Ferrario, Alberto Malovini, Anna Maciąg, Antonio Damato, Alberto Auricchio, Gaia Spinetti, Elena Sangalli, Zexu Dang, Michele Madonna, Mariateresa Ambrosio, Leopoldo Sitia, Paolo Bigini, Gaetano Calì, Stefan Schreiber, Thomas Perls, Sergio Fucile, Francesca Mulas, Almut Nebel, Riccardo Bellazzi, Paolo Madeddu, Carmine Vecchione, Annibale A. Puca
Journal: Circulation Research (2015)

Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury. Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R–like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34 + cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle. Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.
Sustained improvement in left ventricular function and mortality by intracoronary streptokinase administration during evolving myocardial infarction.
Authors: R W Smalling, F Fuentes, M W Matthews, G C Freund, C H Hicks, L A Reduto, W E Walker, R P Sterling, K L Gould
Journal: Circulation (1983)

One hundred eighty-eight patients with acute myocardial infarction were studied prospectively from August 1980 to September 1982. One hundred thirty-six of these patients were entered into a intracoronary streptokinase study after informed consent was obtained. The remaining 52 patients, who either met exclusion criteria for the study or refused to participate, served as a control group and were treated as those in the study group except that they did not undergo emergency cardiac catheterization. Left ventricular function was determined in both groups by gated radionuclide ejection fraction (EF) on admission to the hospital, at discharge, and 6 months after discharge. With successful reperfusion up to 18 hr after onset of chest pain, mean left ventricular function in the study group improved (EF 39 +/- 13% on admission and 46 +/- 12% at discharge; p less than .001). Mean EF in control patients and those not achieving reperfusion did not change from admission to discharge. Mean EF at 6 month follow-up was not significantly different than at discharge in the study group or the control group. Total cardiac mortality in the control group was 19% compared with 10% in the study group (p = .06, NS). When patients admitted in pulmonary edema or shock (Killip class III or IV) were excluded from both groups, total cardiac mortality in the study group was significantly lower (4%) compared with in the control group (12.5%, p less than .05. The administration of intracoronary streptokinase during evolving myocardial infarction up to 18 hr after onset of chest pain may result in decreased mortality and sustained improvement in left ventricular function.