tbuckley/cabot-search huggingface dataset:
THE BIG BANG? AN EVENTFUL YEAR IN WORKERS' COMPENSATION
Authors: Tee L. Guidotti
Journal: Annual Review of Public Health (2006)

Workers' compensation in the past two years has been dominated by events in California, which have been so fundamental as to merit the term big bang. Passage of Senate Bill 899 has led to a comprehensive program of reform in access to medical care, access to rehabilitation services, temporary and permanent disability, evidence-based management, dispute resolution, and system innovation. Two noteworthy developments thus arose: a new requirement for apportionment by cause in causation analysis, and the adoption of evidence-based criteria for impairment assessment, treatment guidelines, and, soon, utilization review. Elsewhere in the United States, changes were modest, but extensive legislative activity in Texas suggests that Texas will be next to make major changes. In Canada, the Workers' Compensation Board of British Columbia has adopted an ambitious strategic initiative, and there is a Canadawide movement to establish presumption for certain diseases in firefighters. Suggestions for future directions include an increased emphasis on prevention, integration of programs, worker participation, enhancing the expertise of health care professionals, evidence-based management, process evaluation, and opportunities for innovation.
A beneficial role for IL-1β in Alzheimer disease?
Authors: Cynthia A. Lemere
Journal: Journal of Clinical Investigation (2007)

While the term neuroinflammation often conjures up images of cellular damage, mounting evidence suggests that certain proinflammatory molecules, such as the cytokine IL-1 beta, may have beneficial and protective effects. In a report in this issue of the JCI, Shaftel and coworkers have generated an elegant mouse model in which local hippocampal overexpression of IL-1 beta in an Alzheimer disease (AD) transgenic mouse model resulted not in the expected exacerbation of the amyloid beta plaque deposition common to AD, but instead in plaque amelioration (see the related article beginning on page 1595). Thus, manipulation of the immune system may be a potential therapeutic approach to protect against AD, although further studies are needed to understand all of the downstream effects of this manipulation.
Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial
Authors: Richard J Powell, William A Marston, Scott A Berceli, Raul Guzman, Timothy D Henry, Amy T Longcore, Theresa P Stern, Sharon Watling, Ronnda L Bartel
Journal: Molecular Therapy (2012)

Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option. Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option.
Increased ventilation with NiIPPV does not necessarily improve exercise capacity in COPD
Authors: M.P. Highcock, J.M. Shneerson, I.E. Smith
Journal: European Respiratory Journal (2003)

Evidence that noninvasive intermittent positive-pressure ventilation (NiIPPV) improves exercise capacity in chronic obstructive pulmonary disease (COPD) is limited. The effectiveness of different ventilators in this setting has not been studied. Three bilevel pressure support ventilators (Bipap S/T 30, Nippy2 and Vpap II ST), applied via a mouthpiece, were compared during submaximal treadmill exercise in eight subjects with COPD. Subjects walked to exhaustion with each of the ventilators and while breathing through the mouthpiece alone, in random order. In addition, four unencumbered walks were performed. The unencumbered distance (mean±sd) walked was 259±123 m. With the mouthpiece alone this decreased to 211±96 m and fell further to 145±76 m with NiIPPV. There was no difference between the brands of ventilator. At the break-point of exercise, significant increases were seen in tidal volume and minute ventilation in the ventilator walks compared with the mouthpiece alone. Noninvasive intermittent positive-pressure ventilation increased ventilation but did not improve exercise capacity in the subjects in this study. No significant differences were seen between the ventilators. The effectiveness of this technique and the optimal method of assistance require further clarification.
Tumor Suppressor Gene Promoter Hypermethylation in Serum of Breast Cancer Patients
Authors: Essel Dulaimi, Jeanne Hillinck, Inmaculada Ibanez de Caceres, Tahseen Al-Saleem, Paul Cairns
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Breast cancer is the most common malignancy in American women and the second leading cause of death from cancer. The genetic and epigenetic alterations that initiate and drive cancer can be used as targets for detection of neoplasia in bodily fluids. Tumor cell-specific aberrant promoter hypermethylation can be detected in nipple aspirate and ductal lavage from breast cancer patients. In this study, we examine serum, a more readily accessible bodily fluid known to contain neoplastic DNA from individuals with cancer, for methylation-based detection of breast neoplasia. Experimental Design: We examined the promoter methylation status of three normally unmethylated biologically significant cancer genes, RAS association domain family protein 1A (RASSF1A), adenomatous polyposis coli (APC), and death-associated protein kinase (DAP-kinase), by sensitive methylation-specific PCR in 34 breast tumor and paired preoperative serum DNA. The 34 patients comprised 7 ductal carcinoma in situ (CIS), 3 lobular CIS, 5 stage I and 15 stage II to IV invasive ductal carcinomas, and 4 invasive lobular carcinomas. Normal and benign tissue and serum control DNA were also examined to determine the specificity of hypermethylation. Results: Hypermethylation of one or more genes was found in 32 of 34 (94%) breast tumor DNA. APC was hypermethylated in 15 of 34 (47%), RASSF1A in 22 of 34 (65%), and DAP-kinase in 17 of 34 (50%) tumors. Twenty-six (76%) of the corresponding serum DNA were positive for promoter hypermethylation, including ductal CIS, lobular CIS, stage I disease, and lobular carcinoma patients. No hypermethylation of APC, RASSF1A, or DAP-kinase was observed in serum DNA from normal healthy women and patients with inflammatory breast disease or nonneoplastic breast tissue specimens. A gene unmethylated in the tumor DNA was always found to be unmethylated in the matched serum DNA (100% specificity). Conclusions: Tumor cell specific promoter hypermethylation of APC, RASSF1A, and DAP-kinase is present in ductal CIS, lobular CIS, and all grades and stages of invasive breast cancer. Hypermethylation can be detected by methylation-specific PCR analysis in serum DNA from patients with preinvasive and early-stage breast cancer amenable to cure. If confirmed in additional studies, hypermethylation-based screening of serum, a readily accessible bodily fluid, may enhance early detection of breast cancer.
Clinical usefulness of high resolution computed tomography in cryptogenic fibrosing alveolitis
Authors: A. Wells
Journal: Thorax (1998)

Despite recent technological advances, agreement amongst clinicians on an algorithm for the optimal management of cryptogenic fibrosing alveolitis (CFA) has proved to be elusive. The non-invasive diagnosis of CFA is often uncertain as the clinical features may mimic those of other interstitial lung diseases. Even when the diagnosis is secure, therapeutic decisions are not straightforward. Reversible inflammatory disease requires aggressive treatment, but side effects from an over-vigorous approach to irreversible fibrotic disease need to be avoided. The extent of disease may influence the approach to treatment, but the optimal means of staging initial severity remains contentious. Furthermore, precision in monitoring changes in disease severity at follow up is unattainable in some cases and this complicates therapeutic decisions. This review explores the impact of high resolution computed tomographic (CT) scanning on the diagnosis and management of CFA.

The integration of a new test into routine management is the product of rigorous initial assessment and subsequent accumulated clinical experience. Enduring changes in clinical practice seldom result solely from “landmark” series. For example, early reports suggested that bronchoalveolar lavage (BAL) might offer invaluable additional diagnostic and prognostic information in diffuse lung disease.1 2 However, subsequent clinical experience has shown that diagnostic and prognostic trends obtained fron BAL in groups of patients are not sufficiently robust to change management substantially in most cases.3 In the same way, although disease activity defined by 67-gallium scanning was shown to correlate with inflammatory cell content on open lung biopsy material,4 it transpired that 67-gallium scanning did not predict responsiveness to treatment.5 Initial enthusiasm generated by early studies of diagnostic tests followed by disappointment is a familiar cycle for clinicians managing patients with interstitial lung disease.

Will this sequence of events apply equally to the use of CT scanning in the management of CFA? …
Elevated Plasma Levels of Transforming Growth Factor-β1 in NIDDM
Authors: Andreas Pfeiffer, Kristina Middelberg-Bisping, Cordula Drewes, Helmut Schatz
Journal: Diabetes Care (1996)

Transforming growth factor-beta (TGF-beta) is a potent inducer of extracellular matrix production and of fibrogenesis and has been associated with the occurrence of diabetic micro- and macrovascular complications. Our aim was to determine whether circulating levels of TGF-beta 1 are altered in NIDDM and, if so, whether they are correlated with blood glucose and show an association with diabetic complications.Plasma levels of TGF-beta 1 were determined by enzyme-linked immunosorbent assay in 44 NIDDM patients and 28 control subjects of comparable age and weight and were correlated with parameters of metabolic control and the occurrence of micro- and macrovascular complications.TGF-beta 1 was significantly elevated in NIDDM (7.9 +/- 1.0 ng/ml), as compared with control subjects (3.1 +/- 0.4 ng/ml, P < 0.001) and correlated with glycosylated hemoglobin (r2 = 0.42; P < 0.001). Thrombocyte levels of TGF-beta 1 were similar in control subjects (54 +/- 7 pg/ml, n = 16) and diabetic patients (61.6 +/- 18 pg/ml, n = 13; P = 0.357). Elevated TGF-beta 1 levels were associated with retinopathy and neuropathy.We conclude that plasma levels of TGF-beta 1 are elevated in NIDDM patients and may be related to average blood glucose. Preliminary data suggest that they may contribute to the occurrence of diabetic complications.
Alterations in the modulation of cerebrovascular tone and blood flow by nitric oxide synthases in SHRsp with stroke
Authors: Noriko Daneshtalab, John S. Smeda
Journal: Cardiovascular Research (2009)

The modulation of myogenic function and cerebral blood flow (CBF) by nitric oxide (NO) synthases (NOS) was assessed in the middle cerebral arteries (MCAs) of Kyoto Wistar stroke prone hypertensive rats (SHRsp) in relation to haemorrhagic stroke development. MCAs were studied with a pressure myograph. CBF in MCA perfusion domain was measured using laser Doppler techniques. NOS isozymes were identified using immunohistochemistry. MCAs expressed endothelial, neuronal, and inducible NOS (eNOS, nNOS, and iNOS, respectively) in the endothelium, nNOS and traces of iNOS in smooth muscle and adventitial cells. Before stroke, MCA pressure-dependent constriction (PDC) was superimposed over basal non-pressure-dependent tone (BNPDT). Endothelial NO generation and non-endothelial nNOS but not iNOS reduced BNPDT and increased the lumen diameter at which PDC initiated without altering the amplitude of PDC. NOS inhibition decreased CBF and increased the upper blood pressure limit of autoregulation. PDC, CBF autoregulation, and NOS dilatory influence were lost, and BNPDT was increased in MCAs from SHRsp with stroke. The expression of NOS isozymes and MCA reactivity to NO donors was not altered. NOS activity was not recovered by in vitrol-arginine or tetrahydrobiopterin supplementation, l-arginase inhibition or superoxide scavengers. The loss of PDC and CBF autoregulation during hypertension may facilitate over-perfusion and cerebral haemorrhage formation in SHRsp. NOS dysfunction in MCAs preceded stroke and involved the inactivation of eNOS and nNOS in areas not subjected to hyper-distension. The elevation in BNPDT due to NOS inactivation may oppose over-perfusion in the absence of CBF autoregulation.
Health Reform and Changes in Health Insurance Coverage in 2014
Authors: Benjamin D. Sommers, Thomas Musco, Kenneth Finegold, Munira Z. Gunja, Amy Burke, Audrey M. McDowell
Journal: New England Journal of Medicine (2014)

On the basis of data from the Gallup–Healthways Well-Being Index, a survey of a national sample of adults, the authors estimate that the rate of uninsured nonelderly adults declined by about 5 percentage points after the Affordable Care Act's initial open-enrollment period.
Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
Authors: Zhichao Liu, Jürgen Borlak, Weida Tong
Journal: Genome Medicine (2014)

Abstract Background Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that primarily affects the lungs and the digestive system, and the current drug treatment is mainly able to alleviate symptoms. To improve disease management for CF, we considered the repurposing of approved drugs and hypothesized that specific microRNA (miRNA) transcription factors (TF) gene networks can be used to generate feed-forward loops (FFLs), thus providing treatment opportunities on the basis of disease specific FFLs. Methods Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks. The target genes were validated using ChIPBase and by employing a consensus approach of diverse algorithms to predict miRNA gene targets. STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs. Using information extracted from SM2miR and Pharmaco-miR, an in silico drug repurposing pipeline was established based on the regulation of miRNA/TFs in CF/CFTR networks. Results In human airway epithelium, a total of 15 composite FFLs were constructed based on CFTR specific miRNA/TF gene networks. Importantly, nine of them were confirmed in patient samples and CF epithelial cells lines, and STRING PPI analysis provided evidence that the targets interacted with each other. Functional analysis revealed that ubiquitin-mediated proteolysis and protein processing in the endoplasmic reticulum dominate the composite FFLs, whose major functions are folding, sorting, and degradation. Given that the mutated CFTR gene disrupts the function of the chloride channel, the constructed FFLs address mechanistic aspects of the disease and, among 48 repurposing drug candidates, 26 were confirmed with literature reports and/or existing clinical trials relevant to the treatment of CF patients. Conclusion The construction of FFLs identified promising drug repurposing candidates for CF and the developed strategy may be applied to other diseases as well.
Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors
Authors: F. Wang, F. Zhou, G. D. Kruh, J. M. Gallo
Journal: Neuro-Oncology (2010)

Vincristine (VCR) is efficacious in some but not all brain cancers and an established substrate of Pgp and Mrp1. However, the extent to which such transporters affect the VCR penetration through the blood-brain barrier (BBB) is poorly understood. To evaluate the role of Pgp and Mrp1 in VCR CNS distribution, VCR concentrations were analyzed under steady-state conditions in normal brain, brain tumor, and bone marrow in wild-type (WT), Mrp1 ko (mrp1-/-), Pgp ko (mdr1a-/-:mdr1b-/-), and TKO (mdr1a-/-:mdr1b-/-:mrp1-/-) mice. VCR normal brain partition coefficients (i.e. tissue/plasma VCR concentrations) in TKO mice were greater than those in WT mice at both targeted 10 and 50 ng/mL plasma VCR concentrations, and ranged from 1.3- to 3.6-fold. VCR brain tumor partition coefficients in Mrp1 mice were greater than WT mice at both doses, being 1.5- and 2.4-fold higher at low and high doses, respectively. TKO mice also showed elevated VCR brain tumor penetration with a brain tumor partition coefficient of 1.9-fold greater than that in WT mice at the high-dose level. The bone marrow partition coefficient in Mrp1 ko mice was 1.65-fold greater than that in WT mice. Within strain comparisons revealed that VCR brain tumor concentrations were significantly greater than normal brain in all strains, ranging from 9- to 40-fold. These findings indicate that disruption of the BBB caused the largest enhancement in VCR tumor concentrations, yet the absence of Mrp1 on the brain tumor vasculature could enhance the penetration compared with that in normal brain.
Serum cytotoxic T lymphocyte–associated antigen 4 in Hymenoptera venom allergy and its modulation by specific immunotherapy
Authors: Daniele Saverino, Anna Maria Riccio, Anthi Rogkakou, Marcello Bagnasco, Patrizia Bonadonna, Rita Simone, Alessandra Chiappori, Cinzia Gamalero, Giovanni Passalacqua, Giorgio Walter Canonica, Giampaola Pesce
Journal: Journal of Allergy and Clinical Immunology (2008)
Independent Effects of Complement Factor H Y402H Polymorphism and Cigarette Smoking on Risk of Age-Related Macular Degeneration
Authors: William K. Scott, Silke Schmidt, Michael A. Hauser, Paul Gallins, Nathalie Schnetz-Boutaud, Kylee L. Spencer, John R. Gilbert, Anita Agarwal, Eric A. Postel, Jonathan L. Haines, Margaret A. Pericak-Vance
Journal: Ophthalmology (2007)
Interferon Regulatory Factor-1 Signaling Regulates the Switch between Autophagy and Apoptosis to Determine Breast Cancer Cell Fate
Authors: Jessica L. Schwartz-Roberts, Katherine L. Cook, Chun Chen, Ayesha N. Shajahan-Haq, Margaret Axelrod, Anni Wärri, Rebecca B. Riggins, Lu Jin, Bassem R. Haddad, Bhaskar V. Kallakury, William T. Baumann, Robert Clarke
Journal: Cancer Research (2015)

Interferon regulatory factor-1 (IRF1) is a tumor suppressor that regulates cell fate in several cell types. Here, we report an inverse correlation in expression of nuclear IRF1 and the autophagy regulator ATG7 in human breast cancer cells that directly affects their cell fate. In mice harboring mutant Atg7, nuclear IRF1 was increased in mammary tumors, spleen, and kidney. Mechanistic investigations identified ATG7 and the cell death modulator beclin-1 (BECN1) as negative regulators of IRF1. Silencing ATG7 or BECN1 caused estrogen receptor-α to exit the nucleus at the time when IRF1 nuclear localization occurred. Conversely, silencing IRF1 promoted autophagy by increasing BECN1 and blunting IGF1 receptor and mTOR survival signaling. Loss of IRF1 promoted resistance to antiestrogens, whereas combined silencing of ATG7 and IRF1 restored sensitivity to these agents. Using a mathematical model to prompt signaling hypotheses, we developed evidence that ATG7 silencing could resensitize IRF1-attenuated cells to apoptosis through mechanisms that involve other estrogen-regulated genes. Overall, our work shows how inhibiting the autophagy proteins ATG7 and BECN1 can regulate IRF1-dependent and -independent signaling pathways in ways that engender a new therapeutic strategy to attack breast cancer.
Glomerular Filtration Rate, Renal Blood Flow and Blood Viscosity during and after Diabetic Coma
Authors: FRANÇOIS C. REUBI
Journal: Circulation Research (1953)

The azotemia of patients in diabetic coma is the result of impaired blood supply, unless tubular impairment antedates or supervenes. Clearance and blood pressure data are presented which strongly suggest that increased blood viscosity is the dominant reason for the reduced renal blood flow.
Heterogeneity of human papillomavirus DNA in a patient with Bowenoid papulosis that progressed to squamous cell carcinoma
Authors: None Park, None Kim, None Youn, None Hwang, None Park, None Ahn, None Kim, None Kim, None Lee, None Choe, None Chung, None Cho
Journal: British Journal of Dermatology (1998)

Bowenoid papulosis (BP) of the genitalia, characterized by the histological findings of a squamous cell carcinoma, follows a largely benign clinical course. The detection of oncogenic human papilloma viruses (HPV) from BP points to an aetiological role of these viral infections. A 47-year-old man with multiple genital skin lesions was seen over a 10-year period with the diagnosis of BP. Recently, he attended again with a recurrent genital tumour that was diagnosed as squamous cell carcinoma. His genital lesions progressed and became polymorphic in appearance, from a wart-like tumour to a reddish invasive plaque. To screen for the presence of different HPV sequences from different skin lesions and to correlate each HPV type with distinct clinical manifestations, polymerase chain reaction and single-strand conformational polymorphism (PCR–SSCP) were performed. PCR–SSCP revealed the presence of several types of HPV from different genital lesions. Sequencing results disclosed that he had a mixed infection of HPV6b, HPV16, HPV18 and HPV33, respectively. Interestingly, the clinical findings were fairly well correlated with the oncogenic potential of HPV found from each lesion.