tbuckley/cabot-search huggingface dataset:
A LIFE COURSE APPROACH TO CHRONIC DISEASE EPIDEMIOLOGY
Authors: John Lynch, George Davey Smith
Journal: Annual Review of Public Health (2005)

▪ Abstract A life course approach to chronic disease epidemiology uses a multidisciplinary framework to understand the importance of time and timing in associations between exposures and outcomes at the individual and population levels. Such an approach to chronic diseases is enriched by specification of the particular way that time and timing in relation to physical growth, reproduction, infection, social mobility, and behavioral transitions, etc., influence various adult chronic diseases in different ways, and more ambitiously, by how these temporal processes are interconnected and manifested in population-level disease trends. In this review, we discuss some historical background to life course epidemiology and theoretical models of life course processes, and we review some of the empirical evidence linking life course processes to coronary heart disease, hemorrhagic stroke, type II diabetes, breast cancer, and chronic obstructive pulmonary disease. We also underscore that a life course approach offers a way to conceptualize how underlying socio-environmental determinants of health, experienced at different life course stages, can differentially influence the development of chronic diseases, as mediated through proximal specific biological processes.
LOCAL AUTOINOCULATION OF THE SENSITIZED ORGANISM WITH FOREIGN PROTEIN AS A CAUSE OF ABNORMAL REACTIONS
Authors: John Auer
Journal: The Journal of Experimental Medicine (1920)

The skin irritant, xylol, when applied to the ears of sensitized and reinjected rabbits often causes a severe inflammation with the formation of crusts and destruction of tissue. Dry gangrene of the entire ear tip may result (Figs. 1, 2, and 3). The same agent, applied in the same dosage and in the same way, to the ears of (1) normal rabbits, (2) normal rabbits injected once with horse serum (serum controls), or (3) sensitized but not reinjected rabbits, causes only a mild inflammation with more or less edema. The inflammation and edema disappear in 2 or 3 days, leaving a practically normal ear. The ear lesions of the sensitized reinjected rabbits which develop after the application of xylol are interpreted as a primary anaphylactic reaction. This primary anaphylactic reaction is considered the result of a local autoinoculation of the ear tissues with circulating antigen. The local autoinoculation is brought about by the irritant action of the xylol which causes an inflammation and edema of the site of application. An anaphylactic reaction may now occur because the inflamed tissues are more active metabolically than normal tissues and therefore the inflamed cells are affected by more antigen per unit of time than the normal cells. A subliminal concentration of antigen for non-inflamed, sensitized cells may thus become effective when inflamed sensitized cells are concerned. This process may theoretically occur in any tissue of a sensitized animal which can show an anaphylactic reaction, for example the intestines, lungs, heart, skin, nerves, arteries, etc. It is possible that this interplay of conditions may explain a number of functional abnormalities in the human subject.
Relation of Body Mass Index in Young Adulthood and Middle Age to Medicare Expenditures in Older Age
Authors: Martha L. Daviglus
Journal: JAMA (2004)

Increasing prevalence of overweight/obesity and rapid aging of the US population have raised concerns of increasing health care costs, with important implications for Medicare. However, little is known about the impact of body mass index (BMI) earlier in life on Medicare expenditures (cardiovascular disease [CVD]-related, diabetes-related, and total) in older age.To examine relationships of BMI in young adulthood and middle age to subsequent health care expenditures at ages 65 years and older.Medicare data (1984-2002) were linked with baseline data from the Chicago Heart Association Detection Project in Industry (CHA) (1967-1973) for 9978 men (mean age, 46.0 years) and 7623 women (mean age, 48.4 years) (baseline overall age range, 33 to 64 years) who were free of coronary heart disease, diabetes, and major electrocardiographic abnormalities, were not underweight (BMI <18.5), and were Medicare-eligible (> or =65 years) for at least 2 years during 1984-2002. Participants were classified by their baseline BMI as nonoverweight (BMI, 18.5-24.9), overweight (25.0-29.9), obese (30.0-34.9), and severely obese (> or =35.0).Cardiovascular disease-related, diabetes-related, and total average annual Medicare charges, and cumulative Medicare charges from age 65 years to death or to age 83 years.In multivariate analyses, average annual and cumulative Medicare charges (CVD-related, diabetes-related, and total) were significantly higher by higher baseline BMI for both men and women. Thus, with adjustment for baseline age, race, education, and smoking, total average annual charges for nonoverweight, overweight, obese, and severely obese women were, respectively, 6224 dollars, 7653 dollars, 9612 dollars, and 12,342 dollars (P<.001 for trend); corresponding total cumulative charges were 76, 866 dollars, 100,959 dollars, 125,470 dollars, and 174,752 dollars (P<.001 for trend). For nonoverweight, overweight, obese, and severely obese men, total average annual charges were, respectively, 7205 dollars, 8390 dollars, 10,128 dollars, and 13,674 dollars (P<.001 for trend). Corresponding total cumulative charges were 100,431 dollars, 109,098 dollars, 119,318 dollars, and 176,947 dollars (P<.001 for trend).Overweight/obesity in young adulthood and middle age has long-term adverse consequences for health care costs in older age.
Proinflammatory Macrophages Enhance the Regenerative Capacity of Human Myoblasts by Modifying Their Kinetics of Proliferation and Differentiation
Authors: Maximilien Bencze, Elisa Negroni, Denis Vallese, Houda Yacoub-Youssef, Soraya Chaouch, Annie Wolff, Ahmed Aamiri, James P Di Santo, Bénédicte Chazaud, Gillian Butler-Browne, Wilson Savino, Vincent Mouly, Ingo Riederer
Journal: Molecular Therapy (2012)

Macrophages have been shown to be essential for muscle repair by delivering trophic cues to growing skeletal muscle precursors and young fibers. Here, we investigated whether human macrophages, either proinflammatory or anti-inflammatory, coinjected with human myoblasts into regenerating muscle of Rag2(-/-) γC(-/-) immunodeficient mice, could modify in vivo the kinetics of proliferation and differentiation of the transplanted human myogenic precursors. Our results clearly show that proinflammatory macrophages improve in vivo the participation of injected myoblasts to host muscle regeneration, extending the window of proliferation, increasing migration, and delaying differentiation. Interestingly, immunostaining of transplanted proinflammatory macrophages at different time points strongly suggests that these cells are able to switch to an anti-inflammatory phenotype in vivo, which then may stimulate differentiation during muscle regeneration. Conceptually, our data provide for the first time in vivo evidence strongly suggesting that proinflammatory macrophages play a supportive role in the regulation of myoblast behavior after transplantation into preinjured muscle, and could thus potentially optimize transplantation of myogenic progenitors in the context of cell therapy.
Breaking the rules: understanding non-compliance with policies and guidelines
Authors: J. Carthey, S. Walker, V. Deelchand, C. Vincent, W. H. Griffiths
Journal: BMJ (2011)

Healthcare organisations use policies and guidelines to standardise and clarify care and improve efficiency, productivity, and safety. But <b>Jane Carthey and colleagues</b> are concerned that their burgeoning number makes it impossible to distinguish the essential from the irrelevant and is affecting compliance
Bulbar and Suprabulbar Control of the Cardiovascular Autonomic Effects during Arterial Hypoxia in the Rabbit
Authors: JOHN B. UTHER, STEPHEN N. HUNYOR, JOHN SHAW, PAUL I. KORNER
Journal: Circulation Research (1970)

The autonomic effects on heart rate, portal, renal, cutaneous and muscle blood flows were studied during approximately constant severe arterial hypoxia in unanesthetized sham-operated, thalamic and pontine rabbits, 3 hours after operations conducted under halothane anesthesia. Neural and adrenal effects were estimated by comparing the responses of different groups of animals: (a) with all neural effectors intact, (b) after adrenalectomy, (c) after selective and (d) after complete pharmacological block of neural effector mechanisms. In pontine animals hypoxia greatly increased cardiac sympathetic activity and seemed to evoke a greater release of adrenal catecholamine (epinephrine) than in other preparations, but caused significant neural peripheral sympathetic constrictor effects in only the portal bed. In thalamic animals, hypoxia caused reflex bradycardia, striking neural constrictor effects in the portal, renal and muscle beds, and cutaneous dilatation. There was little evidence of an increase in epinephrine secretion. It is suggested that there is an inhibitory pathway between diencephalon and bulb that limits the release of epinephrine. Sham-operated animals exposed to hypoxia secreted epinephrine which played an important role in the total reflex response; this group had similar cardioinhibitory and cutaneous effects to thalamic animals, but a more rapid onset of portal and renal constriction and a marked increase in muscle blood flow. The sympathetic responses of the different preparations resulted in different rates of metabolic H + ion production.
An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM)
Authors: T.J. Smith, P.J. Coyne, P.S. Staats, T. Deer, L.J. Stearns, R.L. Rauck, R.L. Boortz-Marx, E. Buchser, E. Català, D.A. Bryce, M. Cousins, G.E. Pool
Journal: Annals of Oncology (2005)
Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia
Authors: Bryce A. Kerlin, S. Betty Yan, Berend H. Isermann, John T. Brandt, Rashmi Sood, Bruce R. Basson, David E. Joyce, Hartmut Weiler, Jean-Francois Dhainaut
Journal: Blood (2003)
Percutaneous in-situ coronary artery bypass (PICAB): a novel myocardial revascularization technique
Authors: S.N. Oesterie, A.C. Yeung, M. Hayase, R.C. Robbins, P. Fitzgerald, P. Yock, R. Kernoff, M. Tumas, R. Virmani, J. Makower
Journal: Journal of the American College of Cardiology (1998)
Restoration of Sensation, Reduced Pain, and Improved Balance in Subjects With Diabetic Peripheral Neuropathy
Authors: David R. Leonard, M. Hamed Farooqi, Sara Myers
Journal: Diabetes Care (2004)

OBJECTIVE—Diabetic peripheral neuropathy (DPN) has been thought to be progressive and irreversible. Recently, symptomatic reversal of DPN was reported after treatments with a near-infrared medical device, the Anodyne Therapy System (ATS). However, the study was not controlled nor was the investigator blinded. We initiated this study to determine whether treatments with the ATS would decrease pain and/or improve sensation diminished due to DPN under a sham-controlled, double-blind protocol. RESEARCH DESIGN AND METHODS—Tests involved the use of the 5.07 and 6.65 Semmes Weinstein monofilament (SWM) and a modified Michigan Neuropathy Screening Instrument (MNSI). Twenty-seven patients, nine of whom were insensitive to the 6.65 SWM and 18 who were sensitive to this filament but insensitive to the 5.07 SWM, were studied. Each lower extremity was treated for 2 weeks with sham or active ATS, and then both received active treatments for an additional 2 weeks. RESULTS—The group of 18 patients who could sense the 6.65 SWM but were insensitive to the 5.07 SWM at baseline obtained a significant decrease in the number of sites insensate after both 6 and 12 active treatments (P &amp;lt; 0.02 and 0.001). Sham treatments did not improve sensitivity to the SWM, but subsequent active treatments did (P &amp;lt; 0.002). The MNSI measures of neuropathic symptoms decreased significantly (from 4.7 to 3.1; P &amp;lt; 0.001). Pain reported on the 10-point visual analog scale decreased progressively from 4.2 at entry to 3.2 after 6 treatments and to 2.3 after 12 treatments (both P &amp;lt; 0.03). At entry, 90% of subjects reported substantial balance impairment; after treatment, this decreased to 17%. However, among the group of nine patients with greater sensory impairment measured by insensitivity to the 6.65 SWM at baseline, improvements in sensation, neuropathic symptoms, and pain reduction were not significant. CONCLUSIONS—ATS treatments improve sensation in the feet of subjects with DPN, improve balance, and reduce pain.
Artificial bile inhibits bile salt–induced gallbladder glycoprotein releasein vitro
Authors: Daniel P. O'Leary
Journal: Hepatology (1994)

The more hydrophobic bile salts cause rapid release of preformed gallbladder mucin and other glycoproteins by gallbladder explants in vitro, whereas the less hydrophobic bile salts elicit a lesser response. This study was designed to determine (a) whether this short-term effect was matched by a sustained increase in glycoprotein secretion over 24 hr and (b) whether it occurred when bile salts were presented in model biles rather than aqueous solution. Although 3 mmol/L taurodeoxycholate in aqueous solution increased release of preformed gallbladder glycoprotein to 843% of control values after 30 min incubation (p < 0.001), no significant increase was observed after 24 hr. The more prolonged exposure also reduced precursor uptake by 32% (p < 0.05) and inhibited synthesis of new glycoprotein by 24% (p < 0.05). Moreover, the stimulatory effect of taurodeoxycholate on release of gallbladder glycoprotein was much reduced when it was presented in model biles rather than in aqueous solution. Nor was there any difference between the effects of more hydrophobic vs. less hydrophobic bile salts when presented in model biles. Aqueous solutions of the more hydrophobic bile salts induce a rapid release of gallbladder glycoprotein in vitro but do not produce a sustained increase in glycoprotein secretion. Their effect is liable to be prevented in vivo by interaction between bile salts and the other lipids in gallbladder bile.
Cancer-Related Axonogenesis and Neurogenesis in Prostate Cancer
Authors: Gustavo E. Ayala, Hong Dai, Michael Powell, Rile Li, Yi Ding, Thomas M. Wheeler, David Shine, Dov Kadmon, Timothy Thompson, Brian J. Miles, Michael M. Ittmann, David Rowley
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Perineural invasion is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer and nerves that results in growth advantage for both. In this article, we present data on a novel biological phenomenon, cancer-related axonogenesis and neurogenesis. Experimental Design: We identify spatial and temporal associations between increased nerve density and preneoplastic and neoplastic lesions of the human prostate. Results: Nerve density was increased in cancer areas as well as in preneoplastic lesions compared with controls. Two- and three-dimensional reconstructions of entire prostates confirmed axonogenesis in human tumors. Furthermore, patients with prostate cancer had increased numbers of neurons in their prostatic ganglia compared with controls, corroborating neurogenesis. Finally, two in vitro models confirmed that cancer cells, particularly when interacting with nerves in perineural invasion, induce neurite outgrowth in prostate cancer. Neurogenesis is correlated with features of aggressive prostate cancer and with recurrence in prostate cancer. We also present a putative regulatory mechanism based on semaphorin 4F (S4F). S4F is overexpressed in cancers cells in the perineural in vitro model. Overexpression of S4F in prostate cancer cells induces neurogenesis in the N1E-115 neurogenesis assay and S4F inhibition by small interfering RNA blocks this effect. Conclusions: This is the first description of cancer-related neurogenesis and its putative regulatory mechanism.
Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo
Authors: Bernhard Nieswandt, Markus Moser, Irina Pleines, David Varga-Szabo, Sue Monkley, David Critchley, Reinhard Fässler
Journal: The Journal of Experimental Medicine (2007)

Platelet adhesion and aggregation at sites of vascular injury are essential for normal hemostasis but may also lead to pathological thrombus formation, causing diseases such as myocardial infarction or stroke. Heterodimeric receptors of the integrin family play a central role in the adhesion and aggregation of platelets. In resting platelets, integrins exhibit a low affinity state for their ligands, and they shift to a high affinity state at sites of vascular injury. It has been proposed that direct binding of the cytoskeletal protein talin1 to the cytoplasmic domain of the integrin β subunits is necessary and sufficient to trigger the activation of integrins to this high affinity state, but direct in vivo evidence in support of this hypothesis is still lacking. Here, we show that platelets from mice lacking talin1 are unable to activate integrins in response to all known major platelet agonists while other cellular functions are still preserved. As a consequence, mice with talin-deficient platelets display a severe hemostatic defect and are completely resistant to arterial thrombosis. Collectively, these experiments demonstrate that talin is required for inside-out activation of platelet integrins in hemostasis and thrombosis.
Elevated Sympathetic Nervous Activity in Mice Deficient in αCGRP
Authors: Yoshio Oh-hashi, Takayuki Shindo, Yukiko Kurihara, Tomihiko Imai, Yuhui Wang, Hiroyuki Morita, Yasushi Imai, Yuji Kayaba, Hiroaki Nishimatsu, Yoshihiro Suematsu, Yasunobu Hirata, Yoshio Yazaki, Ryozo Nagai, Tomoyuki Kuwaki, Hiroki Kurihara
Journal: Circulation Research (2001)

α-Calcitonin gene-related peptide (αCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of αCGRP, we developed an α CGRP -null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained α CGRP -null mice than in corresponding wild-type mice. The elevated MAP in α CGRP -null mice was shown to be the result of elevated peripheral vascular resistance by α-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between α CGRP -null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in α CGRP -null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that αCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.
From GWAS to the clinic: risk factors for intracranial aneurysms
Authors: Ynte M Ruigrok, Gabriel JE Rinkel
Journal: Genome Medicine (2010)

Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating subset of stroke, occurring in relatively young people (mean age around 50 years) of whom around a third die within the initial weeks after the bleed. Environmental and genetic risk factors both have a role in SAH. A recent genome-wide association study of intracranial aneurysms in Finnish, Dutch and Japanese cohorts totaling 5,891 cases and 14,181 controls identified three new loci strongly associated with intracranial aneurysms on chromosomes 18q11.2 and 10q24.32, and replicated two previously found loci on chromosomes 8q11.23-q12.1 and 9p21.3. However, these five intracranial aneurysm risk loci identified so far explain only up to 5% of the familial risk of intracranial aneurysms, which makes genetic risk prediction tests currently unfeasible for intracranial aneurysms. New approaches, including identification of causal variants, rare variants and copy number variants, such as insertions and deletions, may improve genetic risk prediction for SAH and intracranial aneurysms. This may lead to diagnostic tools for identifying individuals at increased risk for aneurysm formation and rupture of aneurysms. In this way, genetic diagnostic tools will identify the people who will benefit most from screening by imaging studies for aneurysms and those who are most likely to benefit from preventive treatment of incidentally discovered aneurysms.
FDA Increases Focus on Postmarketing Studies
Authors: M. Goozner
Journal: JNCI Journal of the National Cancer Institute (2010)

Under pressure from Capitol Hill, the U.S. Food and Drug Administration is pushing drug companies to channel more resources into completing confirmatory trials for cancer drugs approved under the accelerated approval program. The fi rst results of the campaign have raised anew a question that has dogged the program since its inception in 1992: Do improvements in surrogate markers in small or short clinical trials, which are the basis for accelerated approvals, translate into a survival benefi t or improved quality of life for patients? In June, Pfi zer voluntarily withdrew gemtuzumab ozogamicin (Mylotarg) from the market after a U.S. cooperative group study submitted to the FDA showed that the drug worsened outcomes for acute myeloid leukemia patients. Wyeth, which Pfi zer later acquired, had been granted accelerated approval for the drug in 2000. Pfi zer will continue producing the drug for acute myeloid leukemia patients already on the regimen but agreed to discontinue marketing it to new patients. Then, in mid-July, the FDA’s Oncology
Increased Immunogenicity of Tumor-Associated Antigen, Mucin 1, Engineered to Express α-Gal Epitopes: A Novel Approach to Immunotherapy in Pancreatic Cancer
Authors: Takashi Deguchi, Masahiro Tanemura, Eiji Miyoshi, Hiroaki Nagano, Tomohiko Machida, Yoshiaki Ohmura, Shogo Kobayashi, Shigeru Marubashi, Hidetoshi Eguchi, Yutaka Takeda, Toshinori Ito, Masaki Mori, Yuichiro Doki, Yoshiki Sawa
Journal: Cancer Research (2010)

Mucin 1 (MUC1), a bound mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic carcinoma. Evidence suggests that MUC1 can be used as a tumor marker and is a potential target for immunotherapy of pancreatic cancer. However, vaccination with MUC1 peptides fails to stimulate the immune response against cancer cells because immunity toward tumor-associated antigens (TAA), including MUC1, in cancer patients is relatively weak, and the presentation of these TAAs to the immune system is poor due to their low immunogenicity. We investigated whether vaccination with immunogenetically enhanced MUC1 (by expressing alpha-gal epitopes; Galalpha1-3Galbeta1-4GlcNAc-R) can elicit effective antibody production for MUC1 itself as well as certain TAAs derived from pancreatic cancer cells and induced tumor-specific T-cell responses. We also used alpha1,3galactosyltransferase (alpha1,3GT) knockout mice that were preimmunized with pig kidney and transplanted with B16F10 melanoma cells transfected with MUC1 expression vector. Vaccination of these mice with alpha-gal MUC1 resulted in marked inhibition of tumor growth and significant improvement of overall survival time compared with mice vaccinated with MUC1 alone (P = 0.003). Furthermore, vaccination with pancreatic cancer cells expressing alpha-gal epitopes induced immune responses against not only differentiated cancer cells but also cancer stem cells. The results suggested that vaccination using cells engineered to express alpha-gal epitopes is a novel strategy for treatment of pancreatic cancer.