tbuckley/cabot-search huggingface dataset:
Insulin Improves Alveolar-Capillary Membrane Gas Conductance in Type 2 Diabetes
Authors: Marco Guazzi, Iacopo Oreglia, Maurizio D. Guazzi
Journal: Diabetes Care (2002)

OBJECTIVE—In type 1 diabetes, lung diffusing capacity for carbon monoxide (DLCO) may be impaired, and insulin has been shown to be beneficial in cases in which near-normal metabolic control is achieved. An influence of insulin, per se, on the alveolar-capillary membrane conductance is unexplored. We aimed at testing this possibility. RESEARCH DESIGN AND METHODS—We studied 19 life-long nonsmoking, asymptomatic patients with type 2 diabetes and normal cardiac function, whose GHb averaged 6.2 ± 0.3% with diet and hypoglycemic drugs. DLCO and its subcomponents (alveolar capillary membrane conductance [DM] and pulmonary capillary blood volume available for gas exchange [Vc]), vital capacity (VC), forced expiratory volume 1 s (FEV1), cardiac output (CO), ejection fraction (EF), pulmonary wedge pressure (WPP), and pulmonary arteriolar resistance (PAR) were determined before and within 60 min after infusion of 50 ml saline + 10 IU of regular insulin or after saline alone on 2 consecutive days (random block design). Glycemia was kept at baseline levels during experiments by dextrose infusion. RESULTS—Percent of normal predicted DLCO averaged 84.2 ± 7.9% and in 14 patients was &amp;lt;100%. Insulin infusion, not saline alone, improved (P &amp;lt; 0.01) DLCO (12%) and DM (14%) and raised DLCO to 98% of the normal predicted value. There were no variations in VC, FEV1, CO, EF, WPP, or PAR, suggesting that the influences of the hormone on gas transfer were not mediated by changes in spirometry, volumes, and hemodynamics of the lung. CONCLUSIONS—Several cases of type 2 diabetes present with increased impedance to gas transfer across the alveolar-capillary membrane, and hypoglycemic drugs do not prevent this inconvenience. Insulin, independently of the metabolic effects, acutely improves gas exchange, possibly through a facilitation of the alveolar-capillary interface conductance.
PARing down EAE
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2006)

An excess of proteinase receptors in the brain aggravates demyelination in multiple sclerosis (MS), suggest Noorbakhsh and colleagues on page 425. Mice lacking proteinase-activated receptor-2 (PAR2), they show, are protected from the brain damage characteristic of experimental autoimmune encephalomyelitis (EAE), a model of MS.






Figure 1

PAR2 (brown) expression on glial cells is increased in patients with multiple sclerosis.




PAR2, a G protein–coupled receptor activated by trypsin-like serine proteases, is best known as the primary pain receptor in the peripheral nervous system. But this receptor is also expressed on smooth muscle cells in the gut, where it stimulates muscle contraction, and on neurons and glial cells in the brain, where it is proposed to promote cell growth and survival.

This versatile receptor can also help promote inflammation. Indeed, activation of PAR2 on skin cells triggers the production of inflammatory cytokines, and PAR2-deficient mice are protected against allergic dermatitis. Noorbakhsh and colleagues now show that PAR2 also enhances inflammation in the brain.

The group noted that brain tissues from both patients with MS and mice with EAE expressed higher than normal levels of PAR2. In mice lacking the receptor, fewer macrophages and T cells invaded the central nervous system, and demyelination was less severe—findings the authors attribute to decreased inflammatory cytokine production by resident glial cells. This finding contrasts with their earlier studies of HIV-associated dementia, in which PAR2 actually protected neurons against cell death.

However, in HIV-associated dementia, PAR2 expression is selectively increased on neurons and promotes cell survival. In EAE, on the other hand, the receptor is increased on glial cells (but not neurons) and promotes inflammatory gene expression.

The authors are now searching for the proteases—many of which are increased during MS and EAE—that activate PAR2. In the meantime, they suggest that interfering with this receptor on glial cells might provide a way to limit brain degeneration in patients with MS.
Antigen- and receptor-driven regulatorymechanisms. The failure of idiotype- coupled spleen cells to induce unresponsiveness in animals lacking the appropriate VH genes is caused by the lack of idiotype-matehed targets
Authors: M-S Sy, MH Dietz, A Nisonoff, RN Germain, B Benacerraf, MI Greene
Journal: The Journal of Experimental Medicine (1980)

A/J anti-p-azobenzenearsonate (ABA) antibodies bearing cross-reactive idiotypic (CRI) determinants, when coupled to spleen cells and then injected intravenously into naive animals, stimulate suppressor T cell (Ts) responses. Moreover, previous studies have demonstrated that the ability of such idiotype-coupled spleen cells to induce immune unresponsiveness to subsequent immunization with ABA-coupled spleen cells is linked to Igh-1 genes. Thus, CRI bearing antibodies from A/J mice, when conjugated to normal BALB/c spleen cells in vitro and then injected intravenously to syngeneic BALB/c mice, failed to induce tolerance in these animals. However, spleen cells taken from these animals transferred significant degrees of suppression to Igh-1 congenic C.AL-20 but not to H-2 congenic, Igh-1 distinct B10.D2 mice. Therefore, the failure of CRI-coupled spleen cells to induce suppressor cell- mediated unresponsiveness in animals unable to express the appropriate VH genes (i.e. BALB/c and B10.D2) appears to be caused by the lack of idiotype- matched targets. The notion that the ability to express certain Vn genes in the recipient animal is a prerequisite for suppressor cell function was further supported by the observation that suppressor cells induced in C.AL-20 mice failed to transfer any degree of suppression to BALB/c mice. The ability to transfer suppression from BALB/c mice to C.AL-20 mice is a T cell- dependent phenomenon, since in vitro treatment with anti-Thy 1.2 antiserum and complement completely abrogated suppressor cell function. Furthermore, these suppressor T cells are antigen specific and can be enriched on idiotype-coated petri dishes, indicating they possess anti-idiotypic receptors. Therefore, appropriate anti-idiotype and idiotype interaction is essential for the manifestation of suppressor T cell function in ABA-specific suppressor pathways.
Reactive Oxygen Species-Induced Activation of p90 Ribosomal S6 Kinase Prolongs Cardiac Repolarization Through Inhibiting Outward K <sup>+</sup> Channel Activity
Authors: Zhibo Lu, Jun-ichi Abe, Jack Taunton, Yan Lu, Tetsuro Shishido, Carolyn McClain, Chen Yan, Sheng Ping Xu, Thomas M. Spangenberg, Haodong Xu
Journal: Circulation Research (2008)

p90 ribosomal S6 kinase (p90RSK) is activated in cardiomyopathies caused by conditions such as ischemia/reperfusion injury and diabetes mellitus in which prolongation of cardiac repolarization and frequent arrhythmias are common. Molecular mechanisms underlying the electric remodeling in cardiac diseases are largely unknown. In the present study, we determined the role of p90RSK activation in the modulation of voltage-gated K + channel activity determining cardiac repolarization. Mice with increased cardiac p90RSK activity due to transgenic expression of p90RSK (p90RSK-Tg) had prolongation of QT intervals and of ventricular myocyte action potential durations. Fast transient outward K + current ( I to,f ), slow delayed outward K + current ( I K,slow ), and steady-state K + current ( I SS ) were significantly decreased in p90RSK-Tg mouse ventricular myocytes. mRNA levels of Kv4.3, Kv4.2, Kv1.5, Kv2.1, and KChIP2 from ventricles between p90RSK-Tg and nontransgenic littermate control mice were similar, as assessed by quantitative reverse transcriptase–polymerase chain reaction, indicating that p90RSK regulates voltage-gated K + channels through posttranslational modification. Kv4.3- and Kv1.5- rather than Kv4.2- and Kv2.1-encoded channels in HEK 293 cells were inhibited by p90RSK. In vitro phosphorylation analysis showed that Kv4.3 was phosphorylated by p90RSK at 2 conserved sites, Ser516 and Ser550 . p90RSK expression significantly inhibited Kv4.3- and Kv4.3 and KChIP2-encoded channel activities in HEK 293 cells, whereas p90RSK’s effects were blocked by amino acid mutation(s) at phosphorylation site(s) in Kv4.3. Hydrogen peroxide, a mediator of induced cardiac p90RSK activation in ischemia/reperfusion injury and diabetes mellitus, had effects similar to those of p90RSK on Kv4.3- or Kv4.3- and KChIP2-encoded channels. Fluoromethylketone, a specific p90RSK inhibitor, abolished hydrogen peroxide effects. These findings indicate that p90RSK activation is critical for reactive oxygen species-mediated inhibition of voltage-gated K + channel activity and leads to prolongation of cardiac repolarization.
Vascular Access and All-Cause Mortality
Authors: Kevan R. Polkinghorne, Stephen P. McDonald, Robert C. Atkins, Peter G. Kerr
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The native arteriovenous fistula (AVF) is the preferred vascular access because of its longevity and its lower rates of infection and intervention. Recent studies suggest that the AVF may offer a survival advantage. Because these data were derived from observational studies, they are prone to potential bias. The use of propensity scores offers an additional method to reduce bias resulting from nonrandomized treatment assignment. Adult (age 18 yr or more) patients who commenced hemodialysis in Australia and New Zealand on April 1, 1999, until March 31, 2002, were studied by using the Australian and New Zealand Dialysis and Transplant Association (ANZDATA) Registry. Cox regression was used to determine the effect of access type on total mortality. Propensity scores were calculated and used both as a controlling variable in the multivariable model and to construct matched cohorts. The catheter analysis was stratified by dialysis duration at entry to ANZDATA to satisfy the proportional-hazard assumption. There were 612 deaths in 3749 patients (median follow-up, 1.07 yr). After adjustment for confounding factors and propensity scores, catheter use was predictive of mortality. Patients with arteriovenous grafts (AVG) also had a significantly increased risk of death. Effect estimates were also consistent in the smaller propensity score–matched cohorts. Both AVG and catheter use in incident hemodialysis patients are associated with significant excess of total mortality. Reducing catheter use and increasing the proportion of patients commencing hemodialysis with a mature AVF remain important clinical objectives.
BCAR1, a Human Homologue of the Adapter Protein p130Cas, and Antiestrogen Resistance in Breast Cancer Cells
Authors: Arend Brinkman, Silvia van der Flier, Elisabeth M. Kok, Lambert C. J. Dorssers
Journal: JNCI Journal of the National Cancer Institute (2000)

Treatment of breast cancer with the antiestrogen tamoxifen is effective in approximately one half of the patients with estrogen receptor-positive disease, but tumors recur frequently because of the development of metastases that are resistant to tamoxifen. We have previously shown that mutagenesis of human estrogen-dependent ZR-75-1 breast cancer cells by insertion of a defective retrovirus genome caused the cells to become antiestrogen resistant. In this study, we isolated and characterized the crucial gene at the breast cancer antiestrogen resistance 1 (BCAR1) locus.Transfer of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen-resistant phenotype on the recipient cells. The complete coding sequence of BCAR1 was isolated by use of exon-trapping and complementary DNA (cDNA) library screening. Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino acids that was strongly homologous to rat p130Cas-adapter protein. Genomic analysis revealed that BCAR1 consists of seven exons and is located at chromosome 16q23.1. BCAR1 transcripts were detected in multiple human tissues and were similar in size to transcripts produced by retrovirus-mutated ZR-75-1 cells. Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell proliferation in the presence of antiestrogens, confirming that BCAR1 was the responsible gene in the locus.Overexpression of the BCAR1 gene confers antiestrogen resistance on human ZR-75-1 breast cancer cells. Overexpression of BCAR1 in retrovirus-mutated cells appears to result from activation of the gene's promoter. The isolation and characterization of this gene open new avenues to elucidating mechanisms by which the growth of human breast cancer becomes independent of estrogen.
Delivering High-Quality and Affordable Care Throughout the Cancer Care Continuum
Authors: Ya-Chen Tina Shih, Patricia A. Ganz, Denise Aberle, Amy Abernethy, Justin Bekelman, Otis Brawley, James S. Goodwin, Jim C. Hu, Deborah Schrag, Jennifer S. Temel, Lowell Schnipper
Journal: Journal of Clinical Oncology (2013)

The national cost of cancer care is projected to reach $173 billion by 2020, increasing from $125 billion in 2010. This steep upward cost trajectory has placed enormous an financial burden on patients, their families, and society as a whole and raised major concern about the ability of the health care system to provide and sustain high-quality cancer care. To better understand the cost drivers of cancer care and explore approaches that will mitigate the problem, the National Cancer Policy Forum of the Institute of Medicine held a workshop entitled "Delivering Affordable Cancer Care in the 21st Century" in October 2012. Workshop participants included bioethicists, health economists, primary care physicians, and medical, surgical, and radiation oncologists, from both academic and community settings. All speakers expressed a sense of urgency about the affordability of cancer care resulting from the future demographic trend as well as the high cost of emerging cancer therapies and rapid diffusion of new technologies in the absence to evidence indicating improved outcomes for patients. This article is our summary of presentations at the workshop that highlighted the overuse and underuse of screening, treatments, and technologies throughout the cancer care continuum in oncology practice in the United States.
Epolones induce erythropoietin expression via hypoxia-inducible factor-1α activation
Authors: Roger M. Wanner, Patrick Spielmann, Deborah M. Stroka, Gieri Camenisch, Isabelle Camenisch, Annette Scheid, David R. Houck, Christian Bauer, Max Gassmann, Roland H. Wenger
Journal: Blood (2000)
MB-23 * CO-INHIBITION OF THE SONIC HEDGEHOG AND CXCR4 PATHWAYS UNIQUELY BLOCKS TUMOR INITIATING CELL FUNCTION IN MEDULLOBLASTOMA
Authors: S. Ward, J. Rubin
Journal: Neuro-Oncology (2015)

Medulloblastoma is the most common malignant brain tumor of childhood. Even with current intensive treatments there is significant morbidity and mortality associated with this diagnosis. Recent hope for improved outcome derives from the stratification of medulloblastoma into four molecular subtypes and the promise that subtype-specific targeted therapy will be more efficacious and less toxic. However, even within specific subtypes there can be variable outcomes, suggesting that further subclasification will be required. We previously showed that CXCR4, a G-protein coupled receptor, is differentially expressed in the Sonic hedgehog (Shh) subtype of medulloblastoma and its activation is required for maximal medulloblastoma growth in vitro and in vivo. We investigated the utility of combining inhibition of both the Shh and CXCR4 pathways in a preclinical model of Shh-medulloblastoma. We measured anti-tumor activity and effects on tumor subtransplantation efficiency of single agents and combined treatment with the Shh antagonist GDC-0449 (vismodegib) and the CXCR4 antagonist AMD3100. We found that combined therapy had the greatest anti-tumor effect and that only inhibition of both pathways abrogated tumorigenicity upon subtransplantation. These results indicated that dual-inhibition was affecting the tumor initiating cell (TIC) population. We used flow cytometry to further investigate this possibility and found that dual inhibition resulted in the loss of a subpopulation of cells with high CXCR4 and CD15 surface expression. Concordant with this diminution in the putative TIC population we found decreased expression of the stem cell markers Sox2, Nanog and Oct4 in doubly treated tumors. Decreased expression of these stem cell markers was associated with increased presence of the repressive histone mark H3K27me3 at their promoters. Together these data indicate that the Shh and CXCR4 signaling pathways in medulloblastoma converge in the subpopulation of TICs to regulate stem cell activity. Dual inhibition may therefore represent a powerful new approach to medulloblastoma cure.
Randomized Trial of an Electronic Personal Health Record for Patients With Serious Mental Illnesses
Authors: Benjamin G. Druss, Xu Ji, Gretl Glick, Silke A. von Esenwein
Journal: American Journal of Psychiatry (2014)

For patients with comorbid psychiatric illness and general health conditions, who often receive care across multiple locations and have difficulty managing their illness, having a personal health record was associated with improved quality of preventive care and cardiometabolic care and increased use of general medical services.
Intraoperative Transesophageal Echocardiography Using a Miniaturized Transducer in a Neonate Undergoing Norwood Procedure for Hypoplastic Left Heart Syndrome
Authors: Maxime Cannesson, Roland Hénaine, Olivier Metton, Catherine Védrinne, Bertrand Delanoy, Sylvie Di Fillipo, Jean Neidecker, Jean Ninet, Jean-Jacques Lehot
Journal: Circulation (2008)
Gatekeeping may not be cost effective
Authors: Deborah Josefson
Journal: BMJ (2001)

Restricting access to specialists through “gatekeeping” does not significantly reduce specialist referrals and is not necessarily cost effective, a new study has said ( New England Journal of Medicine 2001;345:1312-7).

Gatekeeping in the United States is the process of requiring insured patients to see a primary care doctor for an initial assessment and examination before being allowed to consult a specialist. As in the NHS in the United Kingdom, the US primary care doctors may choose to treat the patients themselves or to refer them for specialist care. The system has been widely embraced by both health maintenance organisations and traditional insurers as a cost containment method.

In April of 1998 Harvard Vanguard Medical Associates, a multispecialty prepaid group practice (previously …
Regulation of Apoptosis and Caspase-8 Expression in Neuroblastoma Cells by Isoforms of the <i>IG20</i> Gene
Authors: Liang Cheng Li, Jian Rong Sheng, Nirupama Mulherkar, Bellur S. Prabhakar, Matthew N. Meriggioli
Journal: Cancer Research (2008)

Abstract The IG20 gene undergoes alternative splicing resulting in the differential expression of six putative splice variants. Four of these (IG20pa, MADD, IG20-SV2, and DENN-SV) are expressed in virtually all human tissues. However, investigations examining alternative splicing of the IG20 gene to date have been largely limited to nonneural malignant and nonmalignant cells. In this study, we investigated the expression of alternative splice isoforms of the IG20 gene in human neuroblastoma cells. We found that six IG20 splice variants (IG20-SVs) were expressed in two human neuroblastoma cell lines (SK-N-SH and SH-SY5Y), highlighted by the expression of two unique splice isoforms (i.e., KIAA0358 and IG20-SV4). Similarly, we found enriched expression of these two IG20-SVs in human neural tissues derived from cerebral cortex, hippocampus, and, to a lesser extent, spinal cord. Using gain-of-function studies and siRNA technology, we determined that these “neural-enriched isoforms” exerted significant and contrasting effects on vulnerability to apoptosis in neuroblastoma cells. Specifically, expression of KIAA0358 exerted a potent antiapoptotic effect in both the SK-N-SH and SH-SY5Y neuroblastoma cell lines, whereas expression of IG20-SV4 had proapoptotic effects directly related to the activation of caspase-8 in these cells, which have minimal or absent constitutive caspase-8 expression. These data indicate that the pattern of expression of these neural-enriched IG20-SVs regulates the expression and activation of caspase-8 in certain neuroblastoma cells, and that manipulation of IG20-SV expression pattern may represent a potent therapeutic strategy in the therapy of neuroblastoma and perhaps other cancers. [Cancer Res 2008;68(18):7352–61]
Endothelial Dilatory Function Predicts Individual Susceptibility to Renal Damage in the 5/6 Nephrectomized Rat
Authors: Simone Gschwend, Hendrik Buikema, Gerjan Navis, Robert H. Henning, Dick de Zeeuw, Richard P. E. van Dokkum
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. In experimental animal models of renal disease the degree of renal damage varies between individuals. This could be caused by variation in the noxious event or by differences in individual susceptibility. Intact endothelial function is assumed to provide a defense mechanism against progressive renal damage. This study hypothesized that interindividual differences in renal endothelial function might be involved in individual susceptibility to renal damage, and it investigated whether endothelial function of small renal arteries before induction of 5/6 nephrectomy (5/6 Nx) in rats was related to development of renal damage after 5/6 Nx. Wistar rats underwent 5/6 Nx, and small renal arteries of the removed right kidney were investigated for endothelium-dependent relaxation to acetylcholine (ACh, 10−8 to 10−4 mol/L). The contribution of underlying endothelial dilative mediators, NO, prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF), was assessed using the inhibitors, L-NMMA, indomethacin, and charybdotoxin+apamin, respectively. After 5/6 Nx, proteinuria developed in each rat ranging from 22 to 278 (84 ± 14) mg/24 h at week 5 (n = 23). Interestingly, a significant inverse correlation between individual ACh-relaxation (expressed as area under curve in arbitrary units) and proteinuria 5 wk after 5/6 Nx was found (r = −0.54; P = 0.008; n = 23). An inverse correlation was also found between individual NO contribution as well as PG contribution and proteinuria 5 wk after 5/6 Nx (r = −0.86, P = 0.001, n = 11; and r = −0.74, P = 0.01, n = 11, respectively). In addition, individual ACh-relaxation was positively correlated with GFR measured 6 wk after 5/6 Nx (r = 0.58; P = 0.016; n = 17). This study demonstrates for the first time that individual renal endothelial dilatory function of the healthy rat predicts susceptibility to renal damage after 5/6 Nx, which seems to depend on individual endothelial NO and PG activity.
Occupational asthma in the confectionary industry caused by sensitivity to egg
Authors: J. G. Blanco Carmona, S. Juste Picón, M. Garcés Sotillos, P. Rodriguez Gastón
Journal: Allergy (1992)

Blanco Carmona JG, Juste Picón S, Garcés Sotillos M, Rodriguez Gaston P. Occupational asthma in the confectionary industry caused by sensitivity to egg. We report on a patient with asthma induced by occupational exposure to egg used to spray cakes before baking. A type I hypersensitivity to egg white was demonstrated by means of skin test, immunoassay for specific IgE, and immediate bronchial provocation test response to an egg white extract.
Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer
Authors: Ben Slotman, Corinne Faivre-Finn, Gijs Kramer, Elaine Rankin, Michael Snee, Matthew Hatton, Pieter Postmus, Laurence Collette, Elena Musat, Suresh Senan
Journal: New England Journal of Medicine (2007)

We conducted a randomized trial of prophylactic cranial irradiation in patients with extensive small-cell lung cancer who had had a response to chemotherapy.