tbuckley/cabot-search huggingface dataset:
Causal Inference Considerations for Endocrine Disruptor Research in Children's Health
Authors: Stephanie M. Engel, Mary S. Wolff
Journal: Annual Review of Public Health (2013)

Substantial population exposure to endocrine disrupting chemicals, combined with available biomarkers and public concern, has resulted in an explosion of human health effects research. At the same time, remarkable shifts in the regulations governing the composition of some consumer products that contain endocrine disruptors (EDs) has occurred. However, important questions remain as to the weight of evidence linking EDs to human health end points. In this review, we critically examine the literature linking ED exposures to child neurodevelopment, focusing in particular on two model exposures to demonstrate issues related to bioaccumulative [e.g., polychlorinated biphenyls (PCBs)] and rapidly metabolized (e.g., phthalates) compounds, respectively. Issues of study design, confounding, and exposure measurement are considered. Given widespread exposure to these compounds, the potential public health consequences of even small effects on human health are substantial. Therefore, advancing our understanding of any impact calls for careful attention to the principles of causal inference.
The secretary is dead, long live the secretary
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

A consultant paediatrician complained to me that her Trust is ending secretarial support. Clinic letters will now be the responsibility of clinicians – which was poignant as she handed me one of the last letters transcribed by her secretary. It was a triumph for management, another penny-pinching scheme, another worker unemployed.

People working in other industries will have little sympathy. Secretaries and personal assistants are more costly and less fashionable than a Google Calendar or a smartphone. Letters are novelty value, emails are common. The future of healthcare is imagined to promote wireless dialogue between doctor and patient. Less clinic time, more face time via a mobile application.

Such direct access must make for a better world, cutting through the bureaucratic barriers that make it difficult for doctor and patient to end up in the same place at the same time. There's something appealing about pinging an email, or better a direct message on Twitter, to your heart specialist, poking your orthopaedic surgeon on Facebook, or instant messaging your general practitioner.

Education icon, Ken Robinson, divides our existence into a world without us and a world with us. The future, he says, is about developing the world with us. The Internet and digital media offer a means to develop our world, and healthcare—like education—will be one of the sectors that will be transformed most dramatically.

But the digital world has dangers. It is easy to be misinterpreted on email, to misread tone of voice and intent. There is no direct observation, the essence of a clinical art. Exchanges can be cold and unsatisfactory. Healing hands are of no benefit. Conversations can be rigid and unlikely to unravel the deeper issues that sometimes prompt a consultation. The soft skills of doctoring may be lost in a hardwired world.

This is no Luddite plea for the old ways. Communications between patients and their clinicians must be encouraged. Yet, the inevitable consequence is that clinicians, already besieged by information overload in their attempts to stay up to date with clinical practice, will be battered further by communications overload in dealing with inquiries from patients.

Doctors, you might think, should busy themselves with the work of doctoring, not grind themselves down with secretarial duties or sink under a tide of communications. Communication, of course, is a fundamental part of doctoring but managing those communications successfully in our future world will be a major challenge for health services. The medical secretary may not be dead just yet.
Use of blockers in patients with COPD
Authors: D. H Au
Journal: Thorax (2008)

Recent studies suggest that higher visual areas (HVAs) in the mouse visual cortex are anatomically segregated into two visual streams, likely analogous to the ventral and dorsal streams in primates. However, HVAs in mice have yet to be functionally characterized. Moreover, it is unknown when the functional segregation of HVAs occurs during development. Here, we investigated spatiotemporal selectivity of HVAs and their development using wide-field calcium imaging. We found that lateral HVAs in the anatomical ventral stream shared similar spatiotemporal selectivity, whereas the spatiotemporal selectivity of anterior and medial HVAs in the anatomical dorsal stream was not uniform, and these areas were functionally segregated into multiple groups. This functional segregation of HVAs developed and reached an adult-like pattern approximately ten days after eye opening. These results suggest not only the functional segregation of ventral and dorsal streams but also the presence of multiple sub-streams in dorsal stream, and indicate that the functional segregation of visual streams occurs gradually after eye opening. <b>Significance Statement</b> Investigation of the spatiotemporal selectivity of nine higher visual areas (HVAs) in adult and developing mice revealed that lateral HVAs belonging to the putative ventral stream shared similar spatiotemporal selectivity, whereas the spatiotemporal selectivity of anterior and medial HVAs belonging to the putative dorsal stream was not uniform, and these areas were functionally segregated into multiple groups. These results suggest the presence of multiple sub-streams within the putative dorsal stream for visuospatial processing. Furthermore, we found that initially immature functional segregation among HVAs developed to adult-like pattern in approximately ten days after eye opening. These results provide a foundation for using mouse HVAs as a model to understand parallel processing and its developmental mechanism.
Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells
Authors: Philippe Linscheid, Andreas Schaffner, Nenad Blau, Gabriele Schoedon
Journal: Circulation (1998)

Background —The nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is involved in the regulation of endothelium-dependent vascular functions mediated by nitric oxide. Vascular endothelial cells synthesize and secrete large amounts of BH4 on cytokine activation. There is scant knowledge about molecular mechanisms of cytokine-triggered BH4 production in endothelial cells. Methods and Results —Pteridine production, mRNA expression of GTP cyclohydrolase (GTPCH) and 6-pyruvoyltetrahydropterin synthase (PTPS) (both key enzymes of BH4 biosynthesis), and PTPS activity were studied in human umbilical vein endothelial cells (HUVECs) exposed to inflammatory cytokines. BH4 levels were ≤140-fold enhanced on treatment of HUVECs with combined interferon-γ/tumor necrosis factor-α/interleukin-1 (IFN/TNF/IL-1). Specific PTPS activity was ≈3-fold higher in cytokine-treated HUVECs than in untreated cells. Reverse-transcription/limiting-dilution polymerase chain reaction analysis showed that in response to IFN/TNF/IL-1, mRNA abundance of GTPCH and PTPS was increased ≈64-fold and 10-fold, respectively. Conclusions —The present study demonstrates for the first time the cytokine-dependent regulation of PTPS, the second enzyme in BH4 synthesis. Although GTPCH is believed to be the rate-limiting step, control of endothelial PTPS expression by cytokines may play an important role in regulating BH4-dependent nitric oxide production in the vascular system.
Liver Cirrhosis Is Reverted by Urokinase-Type Plasminogen Activator Gene Therapy
Authors: Silvia Salgado, Jesus Garcia, Jose Vera, Fernando Siller, Miriam Bueno, Alejandra Miranda, Aida Segura, Guillermo Grijalva, Jorge Segura, Hector Orozco, Rogelio Hernandez-Pando, Mary Fafutis, Laura K. Aguilar, Estuardo Aguilar-Cordova, Juan Armendariz-Borunda
Journal: Molecular Therapy (2000)

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans. Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.
Proteomics paves the way for Q fever diagnostics
Authors: Malgorzata Kowalczewska, Zuzana Sekeyová, Didier Raoult
Journal: Genome Medicine (2011)

Q fever is a worldwide zoonosis caused by Coxiella burnetii. The disease most frequently manifests clinically as a self-limited febrile illness, as pneumonia (acute Q fever) or as a chronic illness that presents mainly as infective endocarditis. The extreme infectivity of the bacterium results in large outbreaks, and the recent outbreak in the Netherlands underlines its impact on public health. Recent studies on the bacterium have included genome sequencing, the investigation of host-bacterium interactions, the development of cellular and animal models of infection, and the comprehensive analysis of different clinical isolates by whole genome and proteomic approaches. Current approaches for diagnosing Q fever are based on serological methods and PCR techniques, but the diagnosis of early stage disease lacks specificity and sensitivity. Consequently, different platforms have been created to explore Q fever biomarkers. Several studies using a combination of proteomics and recombinant protein screening approaches have been undertaken for the development of diagnostics and vaccines. In this review, we highlight advances in the field of C. burnetii proteomics, focusing mainly on the contribution of these technologies to the development and improvement of Q fever diagnostics.
ANTI-NEUTROPHIL-CYTOPLASM ANTIBODIES IN WEGENER'S GRANULOMATOSIS ARE NOT DIRECTED AGAINST ALKALINE PHOSPHATASE
Authors: Niels Rasmussen, Niels Borregaard, Allan Wiik, WolfgangL Gross, Jens Lüdemann, Jens-M Schröder, R Goldschmeding, P.A.T Tetteroo, A.E.G.Kr Von Dem Borne, C.G.M Kallenberg, C.M Lockwood
Journal: The Lancet (1987)
Is Consolidation Chemotherapy after Concurrent Chemo-Radiotherapy Beneficial for Patients with Locally Advanced Non–Small-Cell Lung Cancer?: A Pooled Analysis of the Literature
Authors: Kazuyuki Tsujino, Takayasu Kurata, Satomi Yamamoto, Tomoya Kawaguchi, Akihito Kubo, Shunichi Isa, Yoshikazu Hasegawa, Sai-Hong Ignatius Ou, Minoru Takada, Masahiko Ando
Journal: Journal of Thoracic Oncology (2013)
Epidemiology of Invasive &lt;EMPH TYPE="ITAL"&gt;Streptococcus pneumoniae&lt;/EMPH&gt; Infections in the United States, 1995-1998&lt;SUBTITLE&gt;Opportunities for Prevention in the Conjugate Vaccine Era&lt;/SUBTITLE&gt;
Authors: Katherine A. Robinson
Journal: JAMA (2001)

][3] The risk of disease is highest among young children, older adults, smokers, and persons with certain chronic illnesses. 4,5A 23-valent polysaccharide vaccine has demonstrated effectiveness against bacteremic infections in older children and adults. 6,7fforts to increase use of this vaccine in the United States have led to more vaccine use in some populations, 8 although coverage remains below the goal of 90% among persons aged 65 years or older. 9Polysaccharide vaccines do not protect children younger than 2 years, a limitation that has motivated efforts to evaluate new vaccines for this age group.Recently, a pneumococcal 7-valent conjugate vaccine was licensed for use in young children.In clinical trials, this vaccine was shown to prevent invasive pneumococcal disease when ad-
Soft Tissue Sarcomas of Childhood and Adolescence: The Prognostic Role of Tumor Size in Relation to Patient Body Size
Authors: Andrea Ferrari, Rosalba Miceli, Cristina Meazza, Elena Zaffignani, Alessandro Gronchi, Luigi Piva, Paola Collini, Marta Podda, Maura Massimino, Roberto Luksch, Graziella Cefalo, Monica Terenziani, Filippo Spreafico, Daniela Polastri, Franca Fossati-Bellani, Michela Casanova, Luigi Mariani
Journal: Journal of Clinical Oncology (2008)

Tumor size is a key prognostic variable for soft tissue sarcomas (STS), and a tumor diameter of 5 cm is generally used as a cutoff for risk grouping purposes. This study aimed to investigate the prognostic effect of tumor size on overall survival and whether such an effect was influenced by the patient's size, expressed as body-surface area (BSA), in a series of 553 pediatric patients with localized STS.Multivariable Cox models were used in which the effect of tumor size was adjusted for patients age, tumor site, histologic subtype, and Intergroup Rhabdomyosarcoma Study grouping, and the interaction between size and BSA was included.Tumor size was confirmed as a significant prognostic factor. Interaction between size and BSA meant that, for a given tumor size, the mortality increased from the larger to the smaller BSA. Conversely, the mortality risk associated with a patient with a BSA of 1.75 m(2) and a 5-cm tumor was the same as for a 0.6 m(2) child with a 2.8-cm tumor.Tumor and body size are jointly informative on outcome. The risk associated with a given tumor size is not the same in patients of different body size, so it may be wrong to use the same 5-cm cutoff for tumor size in risk stratification.
Acidity Generated by the Tumor Microenvironment Drives Local Invasion
Authors: Veronica Estrella, Tingan Chen, Mark Lloyd, Jonathan Wojtkowiak, Heather H. Cornnell, Arig Ibrahim-Hashim, Kate Bailey, Yoganand Balagurunathan, Jennifer M. Rothberg, Bonnie F. Sloane, Joseph Johnson, Robert A. Gatenby, Robert J. Gillies
Journal: Cancer Research (2013)

The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H(+) diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis. Cancer Res; 73(5); 1524-35. ©2012 AACR.
Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA)
Authors: P J Mease, R Fleischmann, A A Deodhar, J Wollenhaupt, M Khraishi, D Kielar, F Woltering, C Stach, B Hoepken, T Arledge, D van der Heijde
Journal: Annals of the Rheumatic Diseases (2013)

To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA).
Central Nervous Integration of the Circulatory and Respiratory Responses to Arterial Hypoxemia in the Rabbit
Authors: PAUL I. KORNER, John B. Uther, Saxon W. White
Journal: Circulation Research (1969)

Neural integration during arterial hypoxia was studied in sham-operated, rhinencephalic, thalamic, high mesencephalic, and pontine rabbits, 3 hours after operation under halothane anesthesia. All preparations except the pontine recovered normal movement and posture 40 to 60 minutes after the operation, and effects on the resting circulation specifically ascribable to transection were small. Activation of diencephalic, and to a lesser extent of rhinencephalic, centers was necessary to produce the large increase in autonomic peripheral resistance effect and the autonomic slowing of heart rate characteristic of normal rabbits. In animals with only pontine and high mesencephalic centers, the autonomic peripheral resistance effect was smaller and there was an autonomic rise in heart rate. The neocortex and rhinencephalon exerted inhibitory influences related to the effects of hyperventilation. Suprabulbar respiratory mechanisms were also activated during hypoxia, with diencephalic mechanisms limiting the reflex response mediated by the pontine centers and the cortex exerting disinhibitory effects on the diencephalic centers. The cardiorespiratory response at different degrees of hypoxia probably depends on differences in relative magnitude of inputs from the arterial chemoreceptors, baroreceptors, and lung inflation receptors, producing different degrees of excitation and inhibition of the various suprabulbar and bulbar centers.
Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure
Authors: Charalambos Gustav Antoniades, Philip A. Berry, Edward T. Davies, Munther Hussain, William Bernal, Diego Vergani, Julia Wendon
Journal: Hepatology (2006)

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non–acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n = 26) and spontaneous survivors (AALF-S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P &lt; .001) and NAALF (22 %, P &lt; .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P &lt; .001) and higher levels of IL-4, IL-6, IL-10 and TNF-α ( P &lt; .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = −0.8 to −0.5, P &lt; .01), IL-10 (r = −0.8, P &lt; .0001), TNF-α (r = −0.4, P = .02). HLA-DR percentage level ≤15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion , the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis.
CD47 Regulates Bone Mass and Tumor Metastasis to Bone
Authors: Özge Uluçkan, Stephanie N. Becker, Hongju Deng, Wei Zou, Julie L. Prior, David Piwnica-Worms, William A. Frazier, Katherine N. Weilbaecher
Journal: Cancer Research (2009)

CD47, also called integrin-associated protein, plays a critical role in the innate immune response and is an atypical member of the immunoglobulin superfamily that interacts with and activates beta3 integrins. beta3 integrin(-/-) mice have defective platelet and osteoclast function and are protected from bone metastasis. The role of CD47 in skeletal homeostasis and bone metastasis has not been described. CD47(-/-) mice had increased bone mass and defective osteoclast function in vivo. Although the number of functional osteoclasts formed by differentiating CD47(-/-) bone marrow macrophages was decreased, high doses of RANKL rescued differentiation and function of CD47(-/-) osteoclasts ex vivo and rescued the osteoclast defect in CD47(-/-) mice. Inhibition of nitric oxide (NO) synthase, which is expressed at higher levels in CD47(-/-) osteoclasts, also rescued the osteoclast defect in CD47(-/-) cells. We then examined the consequences of this osteoclast defect in bone metastasis. In a model of tumor metastasis to bone, bone tumor burden was decreased in the CD47(-/-) mice compared with wild-type (WT) controls, with no decrease in s.c. tumor growth in CD47(-/-) mice. There was decreased tumor-associated bone destruction in the CD47(-/-) mice compared with WT controls, consistent with a defect in osteoclast function that was not rescued by the presence of tumor. Our data show that CD47 regulates osteoclastogenesis, in part, via regulation of NO production, and its disruption leads to a decrease in tumor bone metastasis. CD47 is a novel therapeutic target to strengthen bone mass and diminish metastatic tumor growth in bone.