tbuckley/cabot-search huggingface dataset:
Obesity and Overweight in Relation to Mortality in Men With and Without Type 2 Diabetes/Impaired Glucose Tolerance
Authors: G. David Batty, Mika Kivimaki, George Davey Smith, Michael G. Marmot, Martin J. Shipley
Journal: Diabetes Care (2007)

In studies of apparently healthy individuals, overweight and obesity, typically assessed using BMI, have been consistently associated with an increased risk of all-cause mortality, cardiovascular disease (CVD), and select cancers (1–4). However, extrapolating these results to individuals with type 2 diabetes is complex and perhaps inappropriate. Studies of the influence of obesity and overweight on mortality risk in individuals with type 2 diabetes reveal highly inconsistent findings. With all-cause mortality, obesity shows inverse (5,6), positive (7–10), null (11–16), and “J-” or “U-” shaped (17–19) associations; similarly discrepant results are apparent with coronary heart disease (CHD) (10,12,20,21). This discordance may be at least partially explained by methodological limitations in some studies, such as a modest sample size, a differential categorization of weight across studies, a tendency not to separate diabetes into its two main subtypes, and a failure to adjust for potentially important mediating and confounding variables. Using an extended follow-up of a U.K. prospective cohort study, we addressed this paucity of evidence and methodological shortcomings.

In the Whitehall Study, data were collected on 19,019 male government employees aged 40–69 years when examined between 1967 and 1970, representing a 74% response (22). Height and weight were measured using standard protocols, and BMI was computed (weight [kg]/height2 [m2]) and categorized according to current guidelines (23): normal weight …
Large granular lymphocytosis associated with rheumatoid arthritis.
Authors: A Samanta, I Grant, F E Nichol, J H Pringle, J K Wood, A C Campbell
Journal: Annals of the Rheumatic Diseases (1988)

Ethylene oxide (ETO) is commonly used to sterilize plastic containers, but the effects of residual amounts left after sterilization on protein therapeutics are still not well understood. Here we focus primarily on the factors that influence concentrations of ETO migrating from ETO-treated plastic containers. A study was designed to investigate the kinetics of this process at various temperatures, and the kinetic data could be fit with a model based on a combination of Fickean diffusion and first order chemical reaction (to account for observed hydrolysis of ETO). The diffusion and reaction rate constants thus obtained obey Arrhenius-like temperature dependence. These results indicate that even with the use of an effective extraction protocol and sensitive analytical method, measurements of residual ETO in a container must account for the effects of ETO hydrolysis. Further, the effects of salt concentration and pH of the fluid in the container on accumulated ETO levels were explored. Finally, interactions of ETO with anti-streptavidin (AntiSA) IgG1 and IgG2 antibodies were studied, with ETO adducts found on all methionine residues when incubated in solutions spiked with ETO at concentrations that could be reached (based on the kinetic studies) in ETO-treated plastic vials. Overall, the likelihood of observable ETO-protein modifications upon storage in ETO-sterilized containers will depend on a complex interplay of protein properties, formulation details, storage conditions, and amount of residual ETO initially in the container.
Ammonium chloride, an inhibitor of phagosome-lysosome fusion in macrophages, concurrently induces phagosome-endosome fusion, and opens a novel pathway: studies of a pathogenic mycobacterium and a nonpathogenic yeast.
Authors: P D Hart, M R Young
Journal: The Journal of Experimental Medicine (1991)

The weak base ammonium chloride has been previously reported to inhibit lysosomal movements and phagosome-lysosome (Ph-L) fusion in cultured mouse macrophages (M phi), thus reducing delivery, to an intraphagosomal infection, of endocytosed solutes that have concentrated in secondary lysosomes. We have now addressed the question, whether NH4Cl might affect any direct interaction (if it exists) between such infection phagosomes and earlier, nonlysosomal compartments of the endocytic pathway, i.e., solute-containing endosomes. The phagosomes studied were formed after ingestion of the mouse pathogen Mycobacterium microti and the nonpathogenic yeast Saccharomyces cerevisiae; and the endosomes were formed after nonreceptor-mediated endocytosis of electronopaque and fluorescent soluble markers. By electron microscopy, survey of the cell profiles of M phi that had been treated with 10 mM NH4Cl so that Ph-L fusion was prevented, and that displayed many ferritin-labeled endosomes, revealed numerous examples of the fusion of electronlucent endosomes, revealed numerous examples of the fusion of electronlucent vesicles with phagosomes, whether containing M. microti bacilli or S. cerevisiae yeasts. Fusion was recognized by transfer of label and by morphological evidence of fusion in progress. The fusing vesicles were classed as endosomes, not NH4Cl-lysosomes, by their appearance and provenance, and because lysosome participation was excluded by the concurrent, NH4Cl-caused block of Ph-L fusion and associated lysosomal stasis. No evidence of such phagosome-endosome (Ph-E) fusion was observed in profiles from M phi treated with chloroquine, nor in those from normal, untreated M phi. NH4Cl-treated living M phi that had ingested yeasts at 37 degrees C, followed by endocytosis of lucifer yellow at 17 degrees C (to accumulate labeled endosomes and postpone label passing to lysosomes), were then restored to 37 degrees C. Fluorescence microscopy showed that as many as half of the yeast phagosomes (previously unlabeled) rapidly became colored. We inferred that this transfer was from endosomes (by Ph-E fusion) because Ph-L passage was blocked (by the NH4Cl). We conclude that NH4Cl induces Ph-E fusion at the same time as it suppressed Ph-L fusion. We discuss the mechanisms of these concurrent effects and suggest that they are independent; and we consider the implications of NH4Cl opening a direct route for endocytosed molecules to reach an intraphagosomal infection without involving lysosomes.
Racial Differences in Health: Not Just Black and White, But Shades of Gray
Authors: M Lillie-Blanton, P E Parsons, H Gayle, A Dievler
Journal: Annual Review of Public Health (1996)

Explanations for racial/ethnic disparities in health are varied and complex. This paper reviews the literature to assess the extent to which current disparities are a consequence of racial differences in the social class composition of the US population. We focus this review on African Americans and examine studies that provide information on the effect of race on four outcome measures: infant mortality, hypertension, substance use, and mortality from all-causes. Twenty-three studies were identified that met criteria for inclusion in this review. As expected, most studies provide evidence that socioeconomic conditions are a major factor explaining racial differences in health. Findings, however, vary for the different health indices. Research in the area of substance abuse provides the most consistent evidence that socioeconomic conditions account for observed racial differences. In contrast, studies on infant mortality and hypertension provide a compelling case that the effects of socioeconomic status are important, but not sufficient to explain racial differences. Evidence on mortality from all-causes is equally divided between studies showing no significant race effect and those in which racial differences persist after adjusting for social class. The paper offers possible explanations for the seemingly divergent results and identifies conceptual and methodologic issues for future research seeking to disentangle the complex relations between race, social class, and health.
Lateral Diffusion of GFP-Tagged H2Ld Molecules and of GFP-TAP1 Reports on the Assembly and Retention of These Molecules in the Endoplasmic Reticulum
Authors: Didier Marguet, Elias T Spiliotis, Tsvetelina Pentcheva, Michael Lebowitz, Jonathan Schneck, Michael Edidin
Journal: Immunity (1999)

Lateral diffusion of GFP-tagged H2Ld molecules in the ER membrane reports on their interaction with the TAP complex during synthesis and peptide loading. Peptide-loaded H2Ld molecules diffuse rapidly, near the theoretical limit for proteins in a bilayer. However, these molecules are retained in the ER for some time after assembly. H2Ld molecules, associated with the TAP complex, diffuse slowly, as does GFP-tagged TAP1. This implies that the association of H2Ld molecules with the TAP complex is stable for at least several minutes. It also suggests that the TAP complex is very large, perhaps containing hundreds of proteins.
Seventy-Five Trials and Eleven Systematic Reviews a Day: How Will We Ever Keep Up?
Authors: Hilda Bastian, Paul Glasziou, Iain Chalmers
Journal: PLoS Medicine (2010)

When Archie Cochrane reproached the medical profession for not having critical summaries of all randomised controlled trials, about 14 reports of trials were being published per day. There are now 75 trials, and 11 systematic reviews of trials, per day and a plateau in growth has not yet been reached. Although trials, reviews, and health technology assessments have undoubtedly had major impacts, the staple of medical literature synthesis remains the non-systematic narrative review. Only a small minority of trial reports are being analysed in up-to-date systematic reviews. Given the constraints, Archie Cochrane's vision will not be achieved without some serious changes in course. To meet the needs of patients, clinicians, and policymakers, unnecessary trials need to be reduced, and systematic reviews need to be prioritised. Streamlining and innovation in methods of systematic reviewing are necessary to enable valid answers to be found for most patient questions. Finally, clinicians and patients require open access to these important resources.
An essay on the circulation as behavior
Authors: Bernard T. Engel
Journal: Behavioral and Brain Sciences (1986)

Abstract Most conceptual models of the organization of the cardiovascular system begin with the premise that the nervous system regulates the metabolic and nonmetabolic reflex adjustments of the circulation. These models assume that all the neurally mediated responses of the circulation are reactive, i.e., reflexes elicited by adequate stimuli. This target article suggests that the responses of the circulation are conditional in three senses. First, as Sherrington argued, reflexes are conditional in that they never operate in a vacuum but in a context together with other reflexes. Guided by functional utility, they interact rather than add. Second, as Pavlov argued, stimuli acquire meanings as a result of experience. This notion of stimulus effect plus the Sherringtonian notion of conditionality suggest that association is one of the ways stimuli eliciting cardiovascular reflexes acquire their meanings and thus their relative strengths. Finally, as Skinner and others have argued, operants are responses that act upon the environment to obtain consequences – that is, stimuli. As operants, cardiovascular responses fulfill a major biological need, functioning proactively. The cardiovascular response is an integral component of the animal's behavior regardless of whether it is an elicited reflex or the eliciting stimulus acquired its properties as a result of the genetic inheritance of the animal or through experience, or the cardiovascular response is emitted in anticipation of an environmental consequence. The main theses of this essay are: (1) behavior is an integrated set of responses and the circulation is one of the response systems comprising behavior; (2) behavior is, in part, determined by its functional significance within a context; (3) the contextual factors operative at the time of the behavior have a major role in determining which of the set of possible responses will determine the final act, that is, which behavior will be the effective response and which other behaviors will be concomitants.
Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A.
Authors: Stein Rc, Dowsett M, Davenport J, Hedley A, Ford Ht, Gazet Jc, Coombes Rc
Journal: Cancer Research (1990)

Thirty-one postmenopausal women with advanced breast cancer have been treated with the nonsteroidal competitive aromatase inhibitor CGS 16949A at p.o. doses of 0.3, 1, and 2 mg twice a day. All patients were assessed for response. Five patients, all treated with 1 mg twice daily, had objective evidence of response (two complete responses and three partial responses); disease stabilized in 17 patients. Minor side effects were reported by ten patients. Two further patients treated with 2 mg twice a day experienced persistent nausea which improved after dose reduction, and one patient, treated with 0.3 mg twice daily, developed a vasculitic rash requiring discontinuation of CGS 16949A. Estradiol levels measured in 24 patients were significantly suppressed 2 wk after starting CGS 16949A treatment at all doses used. Treatment with 2 mg twice a day lowered estradiol levels to a mean of 29% of pretreatment values which was significantly lower than the corresponding figure of 57% for patients treated with 0.3 mg twice daily. Aldosterone levels were significantly lowered below pretreatment values by the 1- and 2-mg twice daily doses. No clinically apparent cases of adrenocortical insufficiency occurred, although small changes in serum electrolyte levels were noted. The results indicate that CGS 16949A is an effective aromatase inhibitor, requiring further evaluation in the treatment of advanced breast cancer. The optimal dose is likely to be 1 mg twice a day.
High-Dose Atorvastatin Reduces Periodontal Inflammation
Authors: Sharath Subramanian, Hamed Emami, Esad Vucic, Parmanand Singh, Jayanthi Vijayakumar, Kenneth M Fifer, Achilles Alon, Sudha S Shankar, Michael Farkouh, James H F Rudd, Zahi A Fayad, Thomas E Van Dyke, Ahmed Tawakol
Journal: Journal of the American College of Cardiology (2013)
Oncolytic Virus-Mediated Manipulation of DNA Damage Responses: Synergy With Chemotherapy in Killing Glioblastoma Stem Cells
Authors: Ryuichi Kanai, Samuel D. Rabkin, Stephen Yip, Donatella Sgubin, Cecile M. Zaupa, Yuichi Hirose, David N. Louis, Hiroaki Wakimoto, Robert L. Martuza
Journal: JNCI Journal of the National Cancer Institute (2011)

Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is invariably fatal despite the current optimal multimodal therapy, with the median survival (12-15 months) having barely improved since the 1980s (1).The alkylating agent temozolomide (TMZ) is part of the current standard of care, extending survival by a few months compared with radiation alone (2).The clinical benefits of TMZ are associated with epigenetic silencing of the O 6 -methylguanine-DNA-methyltransferase (MGMT) gene (3,4).Although the inactivating pseudosubstrates of MGMT, O 6 -benzylguanine (BG) and Lomeguatrib (LM), can inhibit MGMT activity (5), hematological toxic effects and lack of increased efficacy at tolerable doses have substantially limited their utility in the clinic (6).GBM stem cells (GSCs), which have been recently isolated, form orthotopic tumors in mice, which closely resemble patients' tumors genotypically and histopathologically, in contrast to GBM cell lines and primary serum-cultured glioma cells (7,8).Accumulating evidence suggests that GSCs are important in disease initiation, progression, recurrence, and resistance to radiation and chemotherapy (9-11).Therefore, targeting GSCs provides an
Glycogen Synthase Kinase-3 Inhibition Induces Glioma Cell Death through c-MYC, Nuclear Factor-κB, and Glucose Regulation
Authors: Svetlana Kotliarova, Sandra Pastorino, Lara C. Kovell, Yuri Kotliarov, Hua Song, Wei Zhang, Rolanda Bailey, Dragan Maric, Jean Claude Zenklusen, Jeongwu Lee, Howard A. Fine
Journal: Cancer Research (2008)

Glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, is involved in diverse cellular processes ranging from nutrient and energy homeostasis to proliferation and apoptosis. Its role in glioblastoma multiforme has yet to be elucidated. We identified GSK3 as a regulator of glioblastoma multiforme cell survival using microarray analysis and small-molecule and genetic inhibitors of GSK3 activity. Various molecular and genetic approaches were then used to dissect out the molecular mechanisms responsible for GSK3 inhibition-induced cytotoxicity. We show that multiple small molecular inhibitors of GSK3 activity and genetic down-regulation of GSK3alpha/beta significantly inhibit glioma cell survival and clonogenicity. The potency of the cytotoxic effects is directly correlated with decreased enzyme activity-activating phosphorylation of GSK3alpha/beta Y276/Y216 and with increased enzyme activity inhibitory phosphorylation of GSK3alpha S21. Inhibition of GSK3 activity results in c-MYC activation, leading to the induction of Bax, Bim, DR4/DR5, and tumor necrosis factor-related apoptosis-inducing ligand expression and subsequent cytotoxicity. Additionally, down-regulation of GSK3 activity results in alteration of intracellular glucose metabolism resulting in dissociation of hexokinase II from the outer mitochondrial membrane with subsequent mitochondrial destabilization. Finally, inhibition of GSK3 activity causes a dramatic decrease in intracellular nuclear factor-kappaB activity. Inhibition of GSK3 activity results in c-MYC-dependent glioma cell death through multiple mechanisms, all of which converge on the apoptotic pathways. GSK3 may therefore be an important therapeutic target for gliomas. Future studies will further define the optimal combinations of GSK3 inhibitors and cytotoxic agents for use in gliomas and other cancers.
Parental refusal to have children immunised: extent and reasons
Authors: N. Simpson, S. Lenton, R. Randall
Journal: BMJ (1995)

One aim of an immunisation programme is to obtain the maximum uptake possible.1 Parents can opt out of having their children immunised, so the programme must also aim to enable parents to make an informed choice. No one has specifically looked at the group of children who receive no immunisations and why their parents make this choice. This study was set up to get this information.

Consent for immunisation of all children born in the Bath District Health Authority is assumed automatically. All newborn babies are entered on to the immunisation call up system run from the Community Child Health computing department. Invitations are sent according to the national schedule. If the invitation is not taken up, then “negative consent” is entered in the child's records. A complete list of children with negative consent was obtained between 1 January 1987 and 1 January 1993. These families were sent a questionnaire with a letter of explanation and a stamped addressed envelope. Those parents who did not reply were sent a second questionnaire. The health visitor was also asked to try to make contact.

During the six years 106 children were found to have had no immunisations. During the same period there …
Therapeutic Impact of Follistatin-Like 1 on Myocardial Ischemic Injury in Preclinical Models
Authors: Yasuhiro Ogura, Noriyuki Ouchi, Koji Ohashi, Rei Shibata, Yoshiyuki Kataoka, Takahiro Kambara, Tetsutaro Kito, Sonomi Maruyama, Daisuke Yuasa, Kazuhiro Matsuo, Takashi Enomoto, Yusuke Uemura, Megumi Miyabe, Masakazu Ishii, Takashi Yamamoto, Yuuki Shimizu, Kenneth Walsh, Toyoaki Murohara
Journal: Circulation (2012)

Background— Acute coronary syndrome is a leading cause of death in developed countries. Follistatin-like 1 (FSTL1) is a myocyte-derived secreted protein that is upregulated in the heart in response to ischemic insult. Here, we investigated the therapeutic impact of FSTL1 on acute cardiac injury in small and large preclinical animal models of ischemia/reperfusion and dissected its molecular mechanism. Methods and Results— Administration of human FSTL1 protein significantly attenuated myocardial infarct size in a mouse or pig model of ischemia/reperfusion, which was associated with a reduction of apoptosis and inflammatory responses in the ischemic heart. Administration of FSTL1 enhanced the phosphorylation of AMP-activated protein kinase in the ischemia/reperfusion–injured heart. In cultured cardiac myocytes, FSTL1 suppressed apoptosis in response to hypoxia/reoxygenation and lipopolysaccharide-stimulated expression of proinflammatory genes through its ability to activate AMP-activated protein kinase. Ischemia/reperfusion led to enhancement of bone morphogenetic protein-4 expression and Smad1/5/8 phosphorylation in the heart, and FSTL1 suppressed the increased phosphorylation of Smad1/5/8 in ischemic myocardium. Treating cardiac myocytes with FSTL1 abolished the bone morphogenetic protein-4–stimulated increase in apoptosis, Smad1/5/8 phosphorylation, and proinflammatory gene expression. In cultured macrophages, FSTL1 diminished lipopolysaccharide-stimulated expression of proinflammatory genes via activation of AMP-activated protein kinase and abolished bone morphogenetic protein-4–dependent induction of proinflammatory mediators. Conclusions— Our data indicate that FSTL1 can prevent myocardial ischemia/reperfusion injury by inhibiting apoptosis and inflammatory response through modulation of AMP-activated protein kinase– and bone morphogenetic protein-4–dependent mechanisms, suggesting that FSTL1 could represent a novel therapeutic target for post-myocardial infarction, acute coronary syndrome.
Signalling and transcriptional regulation in inflammatory and immune cells: importance in lung biology and disease
Authors: K. F. Chung
Journal: European Respiratory Journal (2005)

iving cells respond to their external environment and to signals from other cells by transducing these signals to different parts of the cell, particularly to the nucleus.This idea was initiated by RALL and SUTHERLAND [1], with the concept of cyclic adenosine monophosphate acting as a second messenger to mediate the action of the first messenger that arrived at the cell surface.Much of cell biology is now focused on dissecting out signalling pathways from the cell membrane to the nucleus and also to other parts of the cell, and on how the ultimate cellular response will be determined by the signalling pathways activated.Many signalling pathways regulate cell growth, cell survival, cell differentiation, cell migration, cell metabolism and transcriptional regulation of inflammatory genes, and it will not be surprising that derangement of these pathways can form the basis of disease processes involved in inflammation.