tbuckley/cabot-search huggingface dataset:
Assessing the health benefits of tackling climate change
Authors: A. Charlesworth, A. Gray, D. Pencheon, N. Stern
Journal: BMJ (2011)

Robust measures and interdisciplinary collaboration are needed

Health systems around the world are not short of big challenges, such as managing demand; containing cost; improving access, quality, and transparency; embracing new technology, and engaging patients and the public. More recent challenges to add to this list include population growth; competition for the limited resources of energy, food, and water; and increasingly serious climate change.1 If these problems are left unchecked and unmanaged collaboratively at a global level, compelling evidence shows that this could result in economic and social breakdown, migration, and conflict.2 3 Evidence suggests that these urgent emerging problems could provide an opportunity for health professionals and health systems to also tackle the more traditional challenges that health systems face.

Fortunately, actions that can help mitigate climate change over the longer term can also improve individual and global health now.4 For example, over-consumption of red processed meat is not good for …
VTX-2337 Is a Novel TLR8 Agonist That Activates NK Cells and Augments ADCC
Authors: Hailing Lu, Gregory N. Dietsch, Maura-Ann H. Matthews, Yi Yang, Smita Ghanekar, Margaret Inokuma, Maria Suni, Vernon C. Maino, Katherine E. Henderson, James Jeffry Howbert, Mary L. Disis, Robert M. Hershberg
Journal: Clinical Cancer Research (2011)

Abstract Purpose: We aim to characterize VTX-2337, a novel Toll-like receptor (TLR) 8 agonist in clinical development, and investigate its potential to improve monoclonal antibody–based immunotherapy that includes the activation of natural killer (NK) cells. Experimental Design: HEK-TLR transfectants were used to compare the selectivity and potency of VTX-2337, imiquimod, CpG ODN2006, and CL075. The ability of VTX-2337 to induce cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC) and activation of specific immune cell subsets was examined. The potential for VTX-2337 to activate NK cell activity through direct and indirect mechanisms was also investigated. Finally, we tested the potential for VTX-2337 to augment antibody-dependent cell-mediated cytotoxicity (ADCC), especially in individuals with low-affinity FcγR3A single-nucleotide polymorphism (SNP). Results: VTX-2337 selectively activates TLR8 with an EC50 of about 100 nmol/L and stimulates production of TNFα and interleukin (IL)-12 from monocytes and myeloid dendritic cells (mDC). VTX-2337 stimulates IFNγ production from NK cells and increases the cytotoxicity of NK cells against K562 and ADCC by rituximab and trastuzumab. Effects of VTX-2337 on NK cells were, in part, from direct activation as increased IFNγ production and cytotoxic activity were seen with purified NK cells. Finally, VTX-2337 augments ADCC by rituximab in PBMCs with different FcγR3A genotypes (V/V, V/F, and F/F at position 158). Conclusions: VTX-2337 is a novel small-molecule TLR8 agonist that activates monocytes, DCs, and NK cells. Through the activation of NK cells, it has the potential to augment the effectiveness of monoclonal antibody treatments where a polymorphism in FcγR3A limits clinical efficacy. Clin Cancer Res; 18(2); 499–509. ©2011 AACR.
Feasibility of a portable pedal exercise machine for reducing sedentary time in the workplace
Authors: Lucas J Carr, Kristen A Walaska, Bess H Marcus
Journal: British Journal of Sports Medicine (2011)

Background Sedentary time is independently associated with an increased risk of metabolic disease. Worksite interventions designed to decrease sedentary time may serve to improve employee health. Objective The purpose of this study is to test the feasibility and use of a pedal exercise machine for reducing workplace sedentary time. Methods Eighteen full-time employees (mean age+SD 40.2+10.7 years; 88% female) working in sedentary occupations were recruited for participation. Demographic and anthropometric data were collected at baseline and 4 weeks. Participants were provided access to a pedal exercise machine for 4 weeks at work. Use of the device was measured objectively by exercise tracking software, which monitors pedal activity and provides the user real-time feedback (eg, speed, time, distance, calories). At 4 weeks, participants completed a feasibility questionnaire. Results Participants reported sitting 83% of their working days. Participants used the pedal machines an average of 12.2+6.6 out of a possible 20 working days and pedalled an average of 23.4+20.4 min each day used. Feasibility data indicate that participants found the machines feasible for use at work. Participants also reported sedentary time at work decreased due to the machine. Discussion Findings from this study suggest that this pedal machine may be a feasible tool for reducing sedentary time while at work. These findings hold public health significance due to the growing number of sedentary jobs in the USA and the potential of the device for use in large-scale worksite health programmes.
Recent Origin of a Hominoid-Specific Splice Form of Neuropsin, a Gene Involved in Learning and Memory
Authors: Yi Li, Ya-ping Qian, Xiao-jing Yu, Yin-qiu Wang, Ding-gui Dong, Wei Sun, Run-mei Ma, Bing Su
Journal: Molecular Biology and Evolution (2004)

Neuropsin is a secreted-type serine protease involved in learning and memory. The type II splice form of neuropsin is abundantly expressed in the human brain but not in the mouse brain. We sequenced the type II–spliced region of neuropsin gene in humans and representative nonhuman primate species. Our comparative sequence analysis showed that only the hominoid species (humans and apes) have the intact open reading frame of the type II splice form, indicating that the type II neuropsin originated recently in the primate lineage about 18 MYA. Expression analysis using RT-PCR detected abundant expression of the type II form in the frontal lobe of the adult human brain, but no expression was detected in the brains of lesser apes and Old World monkeys, indicating that the type II form of neuropsin only became functional in recent time, and it might contribute to the progressive change of cognitive abilities during primate evolution.
Nanoparticle-Delivered Suicide Gene Therapy Effectively Reduces Ovarian Tumor Burden in Mice
Authors: Yu-Hung Huang, Gregory T. Zugates, Weidan Peng, David Holtz, Charles Dunton, Jordan J. Green, Naushad Hossain, Michael R. Chernick, Robert F. Padera, Robert Langer, Daniel G. Anderson, Janet A. Sawicki
Journal: Cancer Research (2009)

Abstract There is currently no effective therapy for patients with advanced ovarian cancer. To address the need for a more effective treatment for this deadly disease, we conducted preclinical tests in ovarian tumor–bearing mice to evaluate the therapeutic efficacy of using a cationic biodegradable poly(β-amino ester) polymer as a vector for nanoparticulate delivery of DNA encoding a diphtheria toxin suicide protein (DT-A). The promoter sequences of two genes that are highly active in ovarian tumor cells, MSLN and HE4, were used to target DT-A expression to tumor cells. Administration of DT-A nanoparticles directly to s.c. xenograft tumors and to the peritoneal cavity of mice bearing primary and metastatic ovarian tumors resulted in a significant reduction in tumor mass and a prolonged life span compared to control mice. Minimal nonspecific tissue and blood chemistry toxicity was observed following extended treatment with nanoparticles. DT-A nanoparticle therapy suppressed tumor growth more effectively than treatment with clinically relevant doses of cisplatin and paclitaxel. Our findings suggest that i.p. administration of polymeric nanoparticles to deliver DT-A encoding DNA, combined with transcriptional regulation to target gene expression to ovarian tumor cells, holds promise as an effective therapy for advanced-stage ovarian cancer. [Cancer Res 2009;69(15):6184–91]
Impact of Trait Impulsivity and State Aggression on Divalproex Versus Placebo Response in Borderline Personality Disorder
Authors: Eric Hollander, Alan C. Swann, Emil F. Coccaro, Ping Jiang, Thomas B. Smith
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors’ goal was to determine whether specific pretreatment clinical characteristics differentially predict favorable treatment response to divalproex versus placebo for impulsive aggression in patients with borderline personality disorder. METHOD: Fifty-two outpatients with DSM-IV borderline personality disorder were randomly assigned to receive divalproex (N=20) or placebo (N=32), double-blind, for 12 weeks. Trait impulsivity symptoms were determined by using the Barratt Impulsiveness Scale, and state aggression symptoms were determined by using the Overt Aggression Scale modified for outpatients. Affective stability was determined by using the Young Mania Rating Scale and the Hamilton Depression Rating Scale. Analyses were performed to identify possible baseline symptom domains that predict treatment response. RESULTS: Divalproex was superior to placebo in reducing impulsive aggression in patients with borderline personality disorder. Divalproex-treated patients responded better than placebo-treated patients among those with higher baseline trait impulsivity symptoms and state aggression symptoms. The effects of baseline trait impulsivity and state aggression appear to be independent of one another. However, baseline affective instability did not influence differential treatment response. CONCLUSIONS: Both pretreatment trait impulsivity symptoms and state aggression symptoms predict a favorable response to divalproex relative to placebo for impulsive aggression in patients with borderline personality disorder.
Diagnosis of Primary HIV-1 Infection
Authors: Eric S. Daar, Susan Little, Jacqui Pitt, Joanne Santangelo, Pauline Ho, Nina Harawa, Peter Kerndt, Janis V. Giorgi, Jiexin Bai, Paula Gaut, Douglas D. Richman, Susan Mandel, Stephen Nichols
Journal: Annals of Internal Medicine (2001)

Background: The optimal approach for diagnosing primary HIV-1 infection has not been defined. Objective: To determine the usefulness of symptoms and virologic tests for diagnosing primary HIV-1 infection. Design: Prospective cohort study. Setting: A teaching hospital in Los Angeles and a university research center in San Diego, California. Patients: 436 patients who had symptoms consistent with primary HIV infection. Measurements: Clinical information and levels of HIV antibody, HIV RNA, and p24 antigen. Results: Primary infection was diagnosed in 54 patients (12.4%). The sensitivity and specificity of the p24 antigen assay were 88.7% (95% CI, 77.0% to 95.7%) and 100% (CI, 99.3% to 100%), respectively. For the HIV RNA assay, sensitivity was 100% and specificity was 97.4% (CI, 94.9% to 98.9%). Fever, myalgia, rash, night sweats, and arthralgia occurred more frequently in patients with primary infection (P < 0.05). Conclusions: No sign or symptom allows targeted screening for primary infection. Although assays for HIV RNA are more sensitive than those for p24 antigen in diagnosing primary infection, they are more expensive and are more likely to yield false-positive results. *For participants in the Los Angeles County Primary HIV Infection Recruitment Network, see Appendix.
Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro
Authors: Eugene A. Podrez, David Schmitt, Henry F. Hoff, Stanley L. Hazen
Journal: Journal of Clinical Investigation (1999)

Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2– system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2–)— a major end-product of NO metabolism—resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte–derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2–, occurred at physiological levels of Cl–, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
Growth Properties of Colonic Tumor Cells Are a Function of the Intrinsic Mitochondrial Membrane Potential
Authors: Barbara G. Heerdt, Michele A. Houston, Leonard H. Augenlicht
Journal: Cancer Research (2006)

Abstract Development of malignant transformation in the colonic mucosa includes disruption in the equilibrium between proliferation and apoptosis, decreased expression and deletions of the mitochondrial genome, alterations in mitochondrial enzymatic activity, and elevations in the mitochondrial membrane potential (Δψm). Focusing on the role of the Δψm in tumor development and progression, we generated novel isogenic colonic carcinoma cell lines that exhibit highly significant, stable differences in their intrinsic Δψm. Using these cell lines, we have recently shown that the intrinsic Δψm has a significant influence on steady state mitochondrial activity and the extent to which cells enter butyrate-mediated growth arrest and apoptotic cascades. Here, we report that the Δψm is also profoundly linked to important tumorigenic properties of the cells. Compared with cells with lower Δψm, cells with elevated intrinsic Δψm have an enhanced capacity to (a) respond to hypoxia by avoiding apoptosis and initiating angiogenesis, (b) escape anoikis and grow under anchorage-independent conditions, and (c) invade the basement membrane. Combined with our previous work, these data implicate the intrinsic Δψm of colonic carcinoma cells in determining the probability of tumor expansion and progression. (Cancer Res 2006; 66(3): 1591-6)
Systemic anti-hepatocyte growth factor monoclonal antibody therapy induces the regression of intracranial glioma xenografts.
Authors: K Jin Kim, Lihong Wang, Yi-Chi Su, G Yancey Gillespie, Amandeep Salhotra, Bachchu Lal, John Laterra
Journal: Clinical Cancer Research (2006)

Hepatocyte growth factor (HGF) and its receptor Met are involved in the initiation, progression, and metastasis of numerous systemic and central nervous system tumors. Thus, an anti-HGF monoclonal antibody (mAb) capable of blocking the HGF-Met interaction could have broad applicability in cancer therapy.An anti-HGF mAb L2G7 that blocks binding of HGF to Met was generated by hybridoma technology, and its ability to inhibit the various biological activities of HGF was measured by in vitro assays. The ability of L2G7 to inhibit the growth of tumors was determined by establishing s.c. and intracranial xenografts of human U87 and U118 glioma cell lines in nude mice, and treatment with 100 microg of L2G7 or control given i.p. twice per week.MAb L2G7 strongly inhibited all biological activities of HGF measured in vitro, including cell proliferation, cell scattering, and endothelial tubule formation. Treatment with L2G7 completely inhibited the growth of established s.c. xenografts in nude mice. Moreover, systemic administration of L2G7 from day 5 induced the regression of intracranial U87 xenografts and dramatically prolonged the survival of tumor-bearing mice from a median of 39 to >90 days. L2G7 treatment of large intracranial tumors (average tumor size, 26.7 mm(3)) from day 18 induced substantial tumor regression (control group, 134.3 mm(3); L2G7 treated group, 11.7 mm(3)) by day 29 and again prolonged animal survival.These findings show that blocking the HGF-Met interaction with systemically given anti-HGF mAb can have profound antitumor effects even within the central nervous system, a site previously believed to be resistant to systemic antibody-based therapeutics.
Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-CoA dehydrogenase knockout mouse
Authors: Adrianus J. Bakermans, Michael S. Dodd, Klaas Nicolay, Jeanine J. Prompers, Damian J. Tyler, Sander M. Houten
Journal: Cardiovascular Research (2013)

AimsThe aim of this animal study is to assess fasting-induced changes in myocardial substrate metabolism and energy status as a consequence of mitochondrial long-chain fatty acid β-oxidation deficiency, using magnetic resonance spectroscopy (MRS).
Long term mental health outcomes of Finnish children evacuated to Swedish families during the second world war and their non-evacuated siblings: cohort study
Authors: Torsten Santavirta, Nina Santavirta, Theresa S Betancourt, Stephen E Gilman
Journal: BMJ (2015)

<b>Objectives</b> To compare the risks of admission to hospital for any type of psychiatric disorder and for four specific psychiatric disorders among adults who as children were evacuated to Swedish foster families during the second world war and their non-evacuated siblings, and to evaluate whether these risks differ between the sexes. <b>Design</b> Cohort study. <b>Setting</b> National child evacuation scheme in Finland during the second world war. <b>Participants</b> Children born in Finland between 1933 and 1944 who were later included in a 10% sample of the 1950 Finnish census ascertained in 1997 (n=45 463; women: n=22 021; men: n=23 442). Evacuees in the sample were identified from war time government records. <b>Main outcome measure</b> Adults admitted to hospital for psychiatric disorders recorded between 1971 and 2011 in the Finnish hospital discharge register. <b>Methods</b> We used Cox proportional hazards models to estimate the association between evacuation to temporary foster care in Sweden during the second world war and admission to hospital for a psychiatric disorder between ages 38 and 78 years. Fixed effects methods were employed to control for all unobserved social and genetic characteristics shared among siblings. <b>Results</b> Among men and women combined, the risk of admission to hospital for a psychiatric disorder did not differ between Finnish adults evacuated to Swedish foster families and their non-evacuated siblings (hazard ratio 0.89, 95% confidence interval 0.64 to 1.26). Evidence suggested a lower risk of admission for any mental disorder (0.67, 0.44 to 1.03) among evacuated men, whereas for women there was no association between evacuation and the overall risk of admission for a psychiatric disorder (1.21, 0.80 to 1.83). When admissions for individual psychiatric disorders were analyzed, evacuated girls were significantly more likely than their non-evacuated sisters to be admitted to hospital for a mood disorder as an adult (2.19, 1.10 to 4.33). <b>Conclusions</b> The Finnish evacuation policy was not associated with an increased overall risk of admission to hospital for a psychiatric disorder in adulthood among former evacuees. In fact, evacuation was associated with a marginally reduced risk of admission for any psychiatric disorder among men. Among women who had been evacuated, however, the risk of being admitted to hospital for a mood disorder was increased.
Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids
Authors: S. COOPMAN, H. DEGREEF, A. DOOMS-GOOSSENS
Journal: British Journal of Dermatology (1989)

Contact allergy to topical corticosteroids occurs more frequently than previously supposed. Cross-allergic phenomena are common. On the basis of a review of the literature and our own patch test data on 15 patients, we conclude that positive patchtests to corticosteroids occur approximately six to seven times more frequently in well-defined groups of structurally-related substances than between corticosteroids of different groups. An analogous substitution pattern on the steroid D-ring or the carbon side chain (C20, C21) seems to have a significant influence on the association of positive patchtest results. This is not the case for other structural variables, such as the presence of a double bond in the steroid A-ring or fluoride substitutions on the B-ring. The effect of other factors such as concomitant sensitization and steroid metabolism in the skin on the development of a corticosteroid polyallergy are analysed, and the specificity and sensitivity of cross-allergy phenomena are evaluated. These are important in the selection of a topical steroid in the future treatment of a corticosteroid sensitive patient.
Effect of luminal osmolarity on ion content of connective tissue in rat trachea after epithelial damage
Authors: A.J. Relova, G.M. Roomans
Journal: European Respiratory Journal (2001)

The authors investigated the physical role of the airway epithelium in response to changes in the airway surface fluid9s composition by superperfusing the lumen with nonisotonic solutions. Morphological studies and measurements of changes in ion content in the underlying connective tissue (CT) were carried out. The study used an experimental model of isolated rat trachea. The trachea was mounted in an extraluminal organ bath with Ringer9s solution, whereas the lumen was perfused with a fluid in which the NaCl concentration was varied. The tissue was fixed for electron microscopy or frozen for X-ray microanalysis. X-ray microanalysis showed that the Na and Cl content of the CT increased with increasing luminal NaCl concentrations. This increase was significantly larger when the tight junctions had been damaged by exposure to ethylene glycol tetra-acetic acid. At high luminal NaCl concentrations, electron microscopy showed that a significant influx of fluid into the CT had occurred in tracheae with damaged epithelia. Damage to the epithelium also resulted in ultrastructural changes in myofibroblasts, increased diameter of capillaries, and thickening of the basement membrane. The epithelium evidently plays a crucial role in the regulation of the ion content of the connective tissue in the airway wall, and epithelial damage may explain the greater sensitivity to provocation with hypersomolar sodium chloride solutions or airway dehydration observed in patients with asthma or cystic fibrosis.
Epidermolysis bullosa simplex blister fluid induces an intra-epidermal blister in cultured normal skin
Authors: K. TAKAMORI, K. NAITO, H. OGAWA
Journal: British Journal of Dermatology (1983)

Organ cultures of normal human skin incubated with blister fluid from a patient with epidermolysis bullosa simplex (EBS) produced a clean intra-epidermal blister with histology similar to that of an EBS blister.