tbuckley/cabot-search huggingface dataset:
Treating intracranial hypertension in traumatic brain injury: keep it cool!
Authors: Kees H. Polderman, David K. Menon, Armand R. J. Girbes
Journal: Intensive Care Medicine (2008)

Stocchetti et al. [1] have reported their experience with currently available “second tier” therapeutic options for the treatment of refractory intracranial hypertension in patients with traumatic brain injury (TBI) in three Italian neurotrauma centres. The authors discuss three options to control intracranial pressure: profound hyperventilation, barbiturate coma and decompressive craniectomy. These options were used alone or in combination.

We were surprised that fever management and mild therapeutic hypothermia were not discussed or even mentioned (other than as a potential source of complications) in this article. Various research groups (including one of the centres involved in the present study) have reported that development of fever following TBI is closely linked to intracranial hypertension [2–5]; this would suggest that fever management should be one of the first steps in controlling intracranial hypertension, but this is not mentioned in the article of Stocchetti et al.

Further, it has been conclusively demonstrated (in 14 studies enrolling >1,500 patients) that ICP can be significantly decreased by induction of mild hypothermia [5–10]. Moreover, although the results from studies using hypothermia to improve outcome following severe TBI have been conflicting, the preponderance of evidence strongly suggests that prolonged (3–5 days) cooling can significantly improve neurological outcome in patients with intracranial hypertension [5–10]. None of the therapeutic options discussed by Stocchetti et al. has so far been shown to improve neurological outcome; studies using barbiturate coma [11–13] or hyperventilation [14–15] in patients with refractory intracranial hypertension reported decreases in ICP but no benefits in outcome. Decompressive craniotomy has shown promise in one small study in 27 paediatric patients [16], but has not yet been well studied in adults [17]. Two RCTs addressing this issue are currently in process [18–19].

Hypothermia does not decrease cerebral blood flow without reducing metabolism and oxygen demand, as is the case with hyperventilation [20], and, when used judiciously, tends to cause no hypotension and less myocardial dysfunction than barbiturates. The evidence regarding improved neurological outcome in TBI associated with hypothermia can certainly be debated; but the evidence is (at the very least!) as strong and as favourable as for barbiturates and hyperventilation. Therefore, induced hypothermia should be regarded as one of the “second tier” therapies in refractory intracranial hypertension, and as such deserves to be mentioned as a feasible option in the otherwise excellent discussion by Stocchetti et al.
NFATc3 and NFATc4 Are Required for Cardiac Development and Mitochondrial Function
Authors: Paul B. Bushdid, Hanna Osinska, Ronald R. Waclaw, Jeffery D. Molkentin, Katherine E. Yutzey
Journal: Circulation Research (2003)

Activation of the nuclear factor of activated T-cell (NFAT) family of transcription factors is associated with changes in gene expression and myocyte function in adult cardiac and skeletal muscle. However, the role of NFATs in normal embryonic heart development is not well characterized. In this report, the function of NFATc3 and NFATc4 in embryonic heart development was examined in mice with targeted disruption of both nfatc3 and nfatc4 genes. The nfatc3-/-nfatc4-/- mice demonstrate embryonic lethality after embryonic day 10.5 and have thin ventricles, pericardial effusion, and a reduction in ventricular myocyte proliferation. Cardiac mitochondria are swollen with abnormal cristae, indicative of metabolic failure, but hallmarks of apoptosis are not evident. Furthermore, enzymatic activity of complex II and IV of the respiratory chain and mitochondrial oxidative activity are reduced in nfatc3-/-nfatc4-/- cardiomyocytes. Cardiac-specific expression of constitutively active NFATc4 in nfatc3-/-nfatc4-/- embryos prolongs embryonic viability to embryonic day 12 and preserves ventricular myocyte proliferation, compact zone density, and trabecular formation. The rescued embryos also maintain cardiac mitochondrial ultrastructure and complex II enzyme activity. Together, these data support the hypothesis that loss of NFAT activity in the heart results in a deficiency in mitochondrial energy metabolism required for cardiac morphogenesis and function.
Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome
Authors: K-C. Ong, A.W-K. Ng, L.S-U. Lee, G. Kaw, S-K. Kwek, M.K-S. Leow, A. Earnest
Journal: European Respiratory Journal (2004)

The aim of this study was to investigate pulmonary function and exercise capacity in a group of survivors of the severe acute respiratory syndrome (SARS). At 3 months after hospital discharge, 46 survivors of SARS underwent the following evaluation: spirometry, static lung volumes and carbon monoxide transfer factor (TL,CO). In total, 44 of these patients underwent cardiopulmonary exercise testing. No abnormalities were detected in the pulmonary function tests in 23 (50%) of the patients. Abnormalities of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC and TL,CO were detected in seven (15%), 12 (26%), one (2%) and 18 (39%) patients, respectively. All of these abnormalities were mild except in one case. In 18 patients (41%), the maximum aerobic capacity was below the lower limit of the normal range. Breathing reserve was low in four patients and significant oxygen desaturation was detected in a further four patients. Comparison of the measured exercise capacity with resting pulmonary function tests showed many cases of discordance in impairment. In conclusion, pulmonary function defects were detected in half of the recovered severe acute respiratory syndrome patients 3 months after hospital discharge, but the impairment was mild in almost all cases. Many patients had reduced exercise capacity that cannot be accounted for by impairment of pulmonary function.
Effect of sodium-potassium pump inhibitors and membrane-depolarizing agents on sodium nitroprusside-induced relaxation and cyclic guanosine monophosphate accumulation in rat aorta.
Authors: R M Rapoport, K Schwartz, F Murad
Journal: Circulation Research (1985)

The purpose of this study was to investigate the relationship between sodium nitroprusside-induced relaxation, inhibition of the sodium-potassium pump, and cyclic guanosine monophosphate. Exposure of rat thoracic aorta to ouabain, or potassium- or magnesium-free Krebs-Ringer bicarbonate solution, procedures which presumably inhibit the sodium-potassium pump, or to potassium chloride or tetraethylammonium, membrane-depolarizing agents, inhibited relaxation to nitroprusside. These conditions had little or no effect on the elevated cyclic guanosine monophosphate levels at a concentration of nitroprusside (0.1 microM) that relaxed norepinephrine contracted tissues by 80%. However, at a maximum relaxant concentration of nitroprusside (1.0 microM), these conditions decreased the elevation of cyclic guanosine monophosphate. The inhibition of elevated cyclic guanosine monophosphate levels was independent of the endothelium, extracellular calcium, and the cyclic guanosine monophosphate phosphodiesterase inhibitor, M&B 22,948. The inhibitory effects of ouabain and of potassium- and magnesium-free solution on the increased levels of cyclic guanosine monophosphate caused by 1.0 microM nitroprusside were abolished when tissues were incubated without norepinephrine, or with norepinephrine in the presence of the alpha-adrenergic blocker, phentolamine. In contrast, a beta-adrenergic blocker, propranolol, had no effect on the ouabain-induced inhibition of elevated cyclic guanosine monophosphate levels, with norepinephrine present. These results are consistent with the hypothesis that membrane events regulate cyclic guanosine monophosphate synthesis. At nitroprusside concentrations greater than 0.1 microM, the formation of cyclic guanosine monophosphate appears to be coupled to the status of the smooth muscle cell membrane and integrity of the sodium-potassium pump.(ABSTRACT TRUNCATED AT 250 WORDS)
Functional expression of the murine Thy-1.2 gene in transfected human T cells.
Authors: K C Gunter, R A Kroczek, E M Shevach, R N Germain
Journal: The Journal of Experimental Medicine (1986)

The interaction of certain mAbs with the Thy-1 molecules of murine T lymphocytes leads to cell activation and proliferation. To examine the signal transduction mechanism underlying this process and to determine what, if any, relationship exists between Thy-1-dependent triggering and T cell activation mediated through the T3-antigen receptor (T3-Ti) complex, a genomic clone of murine Thy-1.2 was isolated and transfected into the human T cell tumor, Jurkat. The transfected gene was actively transcribed in these human cells and high levels of Thy-1.2 glycoprotein were found on the cell membrane. Although certain mAbs to Thy-1.2 failed to bind to the Thy-1 transfected Jurkat cells, several known mitogenic anti-Thy-1 mAbs did react, and in the presence of phorbol ester, induced IL-2 secretion. One Thy-1+ transfectant out of five failed to produce IL-2 in response to anti-T3/Ti antibodies even though it retained the ability to increase intracytoplasmic calcium concentration [( Ca2+]i) in response to these ligands. A Thy-1 negative revertant of this cell regained anti-T3/Ti reactivity, suggesting a regulatory defect in signal transmission via T3/Ti in the original transfectant. These data confirm the ability of Thy-1 to act as an activation receptor for T cells. They reveal a potential role for changes in [Ca2+]i in this process, in common with other pathways of T cell activation, but also indicate a more complex series of events is involved.
Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy
Authors: Myriam N. Bouchlaka, Gail D. Sckisel, Mingyi Chen, Annie Mirsoian, Anthony E. Zamora, Emanual Maverakis, Danice E.C. Wilkins, Kory L. Alderson, Hui-Hua Hsiao, Jonathan M. Weiss, Arta M. Monjazeb, Charles Hesdorffer, Luigi Ferrucci, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Doug Redelman, Dennis D. Taub, William J. Murphy
Journal: The Journal of Experimental Medicine (2013)

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
Allogenic bone marrow transplantation: not a treatment yet for familial Mediterranean fever
Authors: Isabelle Touitou, Eldad Ben-Chetrit, Ruth Gershoni-Baruch, Gilles Grateau, Daniel L. Kastner, Isabelle Kone-Paut, Avi Livneh, Raffaele Manna, Issam Mansour, Huri Ozdogan, Seza Ozen, Tamara Sarkisian, Mehmet Tunca, Fatos Yalcinkaya
Journal: Blood (2003)
Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer
Authors: Jamin D. Steffen, Renee M. Tholey, Marie-France Langelier, Jamie L. Planck, Matthew J. Schiewer, Shruti Lal, Nikolai A. Bildzukewicz, Charles J. Yeo, Karen E. Knudsen, Jonathan R. Brody, John M. Pascal
Journal: Cancer Research (2013)

PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.
NEURAL NETWORK DYNAMICS
Authors: Tim P. Vogels, Kanaka Rajan, L.F. Abbott
Journal: Annual Review of Neuroscience (2005)

Neural network modeling is often concerned with stimulus-driven responses, but most of the activity in the brain is internally generated. Here, we review network models of internally generated activity, focusing on three types of network dynamics: (a) sustained responses to transient stimuli, which provide a model of working memory; (b) oscillatory network activity; and (c) chaotic activity, which models complex patterns of background spiking in cortical and other circuits. We also review propagation of stimulus-driven activity through spontaneously active networks. Exploring these aspects of neural network dynamics is critical for understanding how neural circuits produce cognitive function.
Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate
Authors: Paul A. Meyers, Cindy L. Schwartz, Mark Krailo, Eugenie S. Kleinerman, Donna Betcher, Mark L. Bernstein, Ernest Conrad, William Ferguson, Mark Gebhardt, Allen M. Goorin, Michael B. Harris, John Healey, Andrew Huvos, Michael Link, Joseph Montebello, Helen Nadel, Michael Nieder, Judith Sato, Gene Siegal, Michael Weiner, Robert Wells, Lester Wold, Richard Womer, Holcombe Grier
Journal: Journal of Clinical Oncology (2005)

To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS).Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS.Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%.The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.
Cellular Cardiomyoplasty Improves Survival After Myocardial Injury
Authors: Wilhelm Roell, Zhong J. Lu, Wilhelm Bloch, Sharon Siedner, Klaus Tiemann, Ying Xia, Eva Stoecker, Michaela Fleischmann, Heribert Bohlen, Robert Stehle, Eugen Kolossov, Gottfried Brem, Klaus Addicks, Gabriele Pfitzer, Armin Welz, Juergen Hescheler, Bernd K. Fleischmann
Journal: Circulation (2002)

Background — Cellular cardiomyoplasty is discussed as an alternative therapeutic approach to heart failure. To date, however, the functional characteristics of the transplanted cells, their contribution to heart function, and most importantly, the potential therapeutic benefit of this treatment remain unclear. Methods and Results — Murine ventricular cardiomyocytes (E12.5–E15.5) labeled with enhanced green fluorescent protein (EGFP) were transplanted into the cryoinjured left ventricular walls of 2-month-old male mice. Ultrastructural analysis of the cryoinfarction showed a complete loss of cardiomyocytes within 2 days and fibrotic healing within 7 days after injury. Two weeks after operation, EGFP-positive cardiomyocytes were engrafted throughout the wall of the lesioned myocardium. Morphological studies showed differentiation and formation of intercellular contacts. Furthermore, electrophysiological experiments on isolated EGFP-positive cardiomyocytes showed time-dependent differentiation with postnatal ventricular action potentials and intact β-adrenergic modulation. These findings were corroborated by Western blotting, in which accelerated differentiation of the transplanted cells was detected on the basis of a switch in troponin I isoforms. When contractility was tested in muscle strips and heart function was assessed by use of echocardiography, a significant improvement of force generation and heart function was seen. These findings were supported by a clear improvement of survival of mice in the cardiomyoplasty group when a large group of animals was analyzed (n=153). Conclusions — Transplanted embryonic cardiomyocytes engraft and display accelerated differentiation and intact cellular excitability. The present study demonstrates, as a proof of principle, that cellular cardiomyoplasty improves heart function and increases survival on myocardial injury.
Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate
Authors: Maria Luisa Bianchi, Carla Colombo, Baroukh M Assael, Antonella Dubini, Mariangela Lombardo, Serena Quattrucci, Sergio Bella, Mirella Collura, Barbara Messore, Valeria Raia, Furio Poli, Rita Bini, Carlina V Albanese, Virginia De Rose, Diana Costantini, Giovanna Romano, Elena Pustorino, Giuseppe Magazzù, Serenella Bertasi, Vincenzina Lucidi, Gabriella Traverso, Anna Coruzzo, Amelia D Grzejdziak
Journal: The Lancet Respiratory Medicine (2013)
Islet Transplantation Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes
Authors: Francesca D’Addio, Paola Maffi, Paolo Vezzulli, Andrea Vergani, Alessandra Mello, Roberto Bassi, Rita Nano, Monica Falautano, Elisabetta Coppi, Giovanna Finzi, Armando D’Angelo, Isabella Fermo, Fabio Pellegatta, Stefano La Rosa, Giuseppe Magnani, Lorenzo Piemonti, Andrea Falini, Franco Folli, Antonio Secchi, Paolo Fiorina
Journal: Diabetes Care (2013)

OBJECTIVE Islets after kidney transplantation have been shown to positively affect the quality of life of individuals with type 1 diabetes (T1D) by reducing the burden of diabetes complications, but fewer data are available for islet transplantation alone (ITA). The aim of this study was to assess whether ITA has a positive impact on hemostatic and cerebral abnormalities in individuals with T1D. RESEARCH DESIGN AND METHODS Prothrombotic factors, platelet function/ultrastructure, and cerebral morphology, metabolism, and function have been investigated over a 15-month follow-up period using ELISA/electron microscopy and magnetic resonance imaging, nuclear magnetic resonance spectroscopy, and neuropsychological evaluation (Profile of Mood States test and paced auditory serial addition test) in 22 individuals with T1D who underwent ITA (n = 12) or remained on the waiting list (n = 10). Patients were homogeneous with regard to metabolic criteria, hemostatic parameters, and cerebral morphology/metabolism/function at the time of enrollment on the waiting list. RESULTS At the 15-month follow-up, the group undergoing ITA, but not individuals with T1D who remained on the waiting list, showed 1) improved glucose metabolism; 2) near-normal platelet activation and prothrombotic factor levels; 3) near-normal cerebral metabolism and function; and 4) a near-normal neuropsychological test. CONCLUSIONS ITA, despite immunosuppressive therapy, is associated with a near-normalization of hemostatic and cerebral abnormalities.
Adiponectin and Mortality in Patients with Chronic Kidney Disease
Authors: Vandana Menon, Lijun Li, Xuelei Wang, Tom Greene, Vaidyanathapuram Balakrishnan, Magdalena Madero, Arema A. Pereira, Gerald J. Beck, John W. Kusek, Allan J. Collins, Andrew S. Levey, Mark J. Sarnak
Journal: Journal of the American Society of Nephrology (2006)

Adiponectin is presumed to possess antiatherogenic and cardioprotective properties. Limited data exist on the relationship between adiponectin and mortality in the earlier stages of chronic kidney disease. The Modification of Diet in Renal Disease study was a randomized, controlled trial that was conducted between 1989 and 1993. Adiponectin was measured in frozen samples that were obtained at baseline (<i>N</i> = 820). Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of adiponectin with all-cause and cardiovascular mortality. Mean ± SD age was 52 ± 12 yr, and mean ± SD glomerular filtration rate (GFR) rate was 33 ± 12 ml/min per 1.73 m<sup>2</sup>. Eighty-five percent of participants were white, and 60% were male. Mean ± SD adiponectin was 12.8 ± 8.0 μg/ml. Triglycerides, insulin resistance, glucose, body mass index, GFR, C-reactive protein, and albumin were inversely related and proteinuria and HDL cholesterol were directly related to adiponectin. During the 10-year follow-up period, 201 (25%) participants died of any cause, and 122 (15%) from cardiovascular disease. In multivariable adjusted Cox models, a 1-μg/ml increase in adiponectin was associated with a 3% (hazard ratio 1.03; 95% confidence interval 1.01 to 1.05; <i>P</i> = 0.02) increased risk for all-cause and 6% (hazard ratio 1.06; 95% confidence interval 1.03 to 1.09; <i>P</i> &lt; 0.001) increased risk for cardiovascular mortality. High, rather than low, adiponectin is associated with increased mortality in this cohort of patients with chronic kidney disease stages 3 to 4. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.