tbuckley/cabot-search huggingface dataset:
Functionalism, emergence, and collective coordinates: A statistical physics perspective on “What to say to a skeptical metaphysician”
Authors: Cosma Rohilla Shalizi
Journal: Behavioral and Brain Sciences (2004)

The positions Ross &amp; Spurrett (R&amp;S) take on issues of information, causality, functionalism, and emergence are actually implicit in the theory and practice of statistical physics, specifically in the way it relates macroscopic collective coordinates to microscopic physics. The reasons for taking macroscopic physical variables like temperature or magnetization to be real apply equally to mental properties like pain.
Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model
Authors: Sujatha Kannan, Hui Dai, Raghavendra S. Navath, Bindu Balakrishnan, Amar Jyoti, James Janisse, Roberto Romero, Rangaramanujam M. Kannan
Journal: Science Translational Medicine (2012)

Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer's disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain barrier to the target cells for treating diffuse brain injury is a major challenge. We show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-l-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a marked improvement in motor function in the CP kits. The well-known and safe clinical profile for NAC, when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.
Macrophage Colony-Stimulating Factor Treatment After Myocardial Infarction Attenuates Left Ventricular Dysfunction by Accelerating Infarct Repair
Authors: Toshiyuki Yano, Tetsuji Miura, Peter Whittaker, Takayuki Miki, Jun Sakamoto, Yuichi Nakamura, Yoshihiko Ichikawa, Yoshihiro Ikeda, Hironori Kobayashi, Katsuhiko Ohori, Kazuaki Shimamoto
Journal: Journal of the American College of Cardiology (2006)
Peak expiratory flow and the resistance of the mini-wright peak flow meter
Authors: OF Pedersen, TR Rasmussen, O Omland, T Sigsgaard, PH Quanjer, MR Miller
Journal: European Respiratory Journal (1996)

The purpose of this study was to examine whether the resistance of the peak flow meter influences its recordings. One hundred and twelve subjects, (healthy nonsmokers and smokers and subjects with lung diseases) performed three or more peak expiratory flow (PEF) manoeuvres through a Fleisch pneumotachograph with and without a mini-Wright peak flow meter added in random order as a resistance in series. The results were as follows. In comparison with a pneumotachograph alone, peak flow measured with an added mini-Wright meter had a smaller within-test variation, defined as the difference between the highest and second highest values of PEF in a series of blows. The mean (SE) variation was 14 (1.3) L.min-1 and 19 (1.5) L.min-1 with and without meter added, respectively. In comparison with the pneumotachograph alone, the addition of the mini-Wright meter caused PEF to be underread, especially at high flows. The difference (PEF with meter minus PEF without meter) = -0.064 (average PEF) -8 L.min-1; R2 = 0.13. The mean difference was -7.8 (1.1) %, and increased numerically for a given PEF, when maximal expiratory flow when 75% forced vital capacity remains to be exhaled (MEF75%FVC) decreased. The reproducibility criteria for repeated measurements of peak flow are more appropriately set at 30 L.min-1 than the commonly used 20 L.min-1, because a within-test variation of less than 30 L.min-1 was achieved in 76% of the subjects without PEF meter inserted and in 88% with meter inserted, with no difference between healthy untrained subjects and patients. The resistance of the peak expiratory flow meter causes less variation in recordings but reduces peak expiratory flow, especially at high values and when the peak is large as compared with the rest of the maximal expiratory flow-volume curve.
Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss
Authors: Peijian He, Luqing Zhao, Lixin Zhu, Edward J. Weinman, Roberto De Giorgio, Michael Koval, Shanthi Srinivasan, C. Chris Yun
Journal: Journal of Clinical Investigation (2015)

Diarrhea is one of the troublesome complications of diabetes, and the underlying causes of this problem are complex. Here, we investigated whether altered electrolyte transport contributes to diabetic diarrhea. We found that the expression of Na+/H+ exchanger NHE3 and several scaffold proteins, including NHE3 regulatory factors (NHERFs), inositol trisphosphate (IP3) receptor-binding protein released with IP3 (IRBIT), and ezrin, was decreased in the intestinal brush border membrane (BBM) of mice with streptozotocin-induced diabetes. Treatment of diabetic mice with insulin restored intestinal NHE3 activity and fluid absorption. Molecular analysis revealed that NHE3, NHERF1, IRBIT, and ezrin form macrocomplexes, which are perturbed under diabetic conditions, and insulin administration reconstituted these macrocomplexes and restored NHE3 expression in the BBM. Silencing of NHERF1 or IRBIT prevented NHE3 trafficking to the BBM and insulin-dependent NHE3 activation. IRBIT facilitated the interaction of NHE3 with NHERF1 via protein kinase D2–dependent phosphorylation. Insulin stimulated ezrin phosphorylation, which enhanced the interaction of ezrin with NHERF1, IRBIT, and NHE3. Additionally, oral administration of lysophosphatidic acid (LPA) increased NHE3 activity and fluid absorption in diabetic mice via an insulin-independent pathway. Together, these findings indicate the importance of NHE3 in diabetic diarrhea and suggest LPA administration as a potential therapeutic strategy for management of diabetic diarrhea.
RESPONSE TO MERCURIAL DIURETICS DURING ALKALOSIS: A COMPARISON OF ACUTE METABOLIC AND CHRONIC HYPOKALEMIC ALKALOSIS IN THE DOG 1
Authors: Gilbert H. Mudge, Byron Hardin, Theodora J. Lannon
Journal: Journal of Clinical Investigation (1956)

A relationship between the action of mercurial diuretics and acid-base metabolism has been established for many years. Diuresis may be augmented by the administration of acidifying salts such as ammonium chloride (1), and may be decreased or even totally inhibited by alkalinizing agents (2, 3). Although a variety of clinical and experimental studies suggest that the mercurials act by decreasing the tubular reabsorption of the chloride ion (37), it is not clear exactly why this action of the drug is so susceptible to changes in acid-base balance.
Thyroid Dysfunction, Thyroid Hormone Replacement and Colorectal Cancer Risk
Authors: Ben Boursi, Kevin Haynes, Ronac Mamtani, Yu-Xiao Yang
Journal: JNCI Journal of the National Cancer Institute (2015)

Current screening guidelines for colorectal cancer (CRC) do not consider thyroid dysfunction as a risk factor for disease development. We sought to determine the risk of developing CRC in patients with thyroid dysfunction, with and without thyroid hormone replacement (THR). We conducted a nested case-control study using a large population-based medical records database from the United Kingdom. Study case patients were defined as those with any medical code of CRC. Subjects with familial colorectal cancer syndromes or inflammatory bowel disease (IBD) were excluded. For every case patient, four eligible control patients matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was THR therapy before index date. We further divided the THR unexposed group into patients with hypothyroidism (TSH > 4mg/dl), patients with hyperthyroidism (TSH < 0.4mg/dl), and subjects without documented thyroid abnormality. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRC were estimated using conditional logistic regression. All statistical tests were two-sided. We identified 20990 CRC patients and 82054 control patients. The adjusted odds ratio for CRC associated with THR was 0.88 (95% CI = 0.79 to 0.99, P = .03) and 0.68 (95% CI = 0.55 to 0.83, P < .001) for treatment initiated five to 10 years and more than 10 years before index date, respectively. This protective association increased with cumulative duration of therapy. In contrast, hyperthyroidism (adjusted OR = 1.21, 95% CI = 1.08 to 1.36, P = .001) or untreated hypothyroidism (adjusted OR = 1.16, 95% CI = 1.08 to 1.24, P < .001) were associated with increased risk of CRC. Long-term THR is associated with a decreased risk of CRC. Hyperthyroidism and untreated hypothyroidism are associated with modestly elevated risk of CRC.
Clopidogrel Use and Long-term Clinical Outcomes After Drug-Eluting Stent Implantation
Authors: Eric L. Eisenstein, Kevin J. Anstrom, David F. Kong, Linda K. Shaw, Robert H. Tuttle, Daniel B. Mark, Judith M. Kramer, Robert A. Harrington, David B. Matchar, David E. Kandzari, Eric D. Peterson, Kevin A. Schulman, Robert M. Califf
Journal: JAMA (2006)

Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis.To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease.An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel.Death, nonfatal MI, and the composite of death or MI at 24-month follow-up.Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, -3.3%; 95% CI, -6.3% to -0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, -4.1%; 95% CI, -7.6% to -0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, -0.7%; 95% CI, -2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, -0.5%; 95% CI, -3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, -3.5%; 95% CI, -5.9% to -1.1%; P = .004) and death or MI (0% vs 4.5%; difference, -4.5%; 95% CI, -7.1% to -1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, -1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, -1.6% to 3.6%; P = .44).The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial.
House dust (1–3)‐<i>β</i>‐<scp>d</scp>‐glucan and wheezing in infants
Authors: Y. Y. Iossifova, T. Reponen, D. I. Bernstein, L. Levin, H. Kalra, P. Campo, M. Villareal, J. Lockey, G. K. K. Hershey, G. LeMasters
Journal: Allergy (2007)

Background: (1–3)‐ β ‐ d ‐glucan is a fungal cell wall component, suspected to cause respiratory symptoms in adults. However, very little is known on the possible health effects of (1–3)‐ β ‐ d ‐glucan during infancy. We examined the association between (1–3)‐ β ‐ d ‐glucan exposure and the prevalence of allergen sensitization and wheezing during the first year of life in a birth cohort of 574 infants born to atopic parents. Endotoxin exposure was included as a possible confounder. Methods: (1–3)‐ β ‐ d ‐glucan and endotoxin exposures were measured in settled dust collected from infants’ primary activity rooms. The primary outcomes at approximately age one included parental reports of recurrent wheezing and allergen sensitization evaluated by skin prick testing to a panel of 15 aeroallergens as well as milk and egg white. Results: Exposure to high (1–3)‐ β ‐ d ‐glucan concentration (within fourth quartile) was associated with reduced likelihood of both recurrent wheezing [adjusted OR (aOR) = 0.39, 95% CI = 0.16–0.93] and recurrent wheezing combined with allergen sensitization (aOR = 0.13, 95% CI = 0.03–0.61). Similar trends were found between (1–3)‐ β ‐ d ‐glucan concentrations and allergen sensitization (aOR = 0.57, 95% CI = 0.30–1.10). In contrast, recurrent wheezing with or without allergen sensitization was positively associated with low (1–3)‐ β ‐ d ‐glucan exposure within the first quartile (aOR = 3.04, 95% CI = 1.25–7.38; aOR = 4.89, 95% CI = 1.02–23.57). There were no significant associations between endotoxin exposure and the studied health outcomes. Conclusions: This is the first study to report that indoor exposure to high levels of (1–3)‐ β ‐ d ‐glucan (concentration &gt;60 μ g/g) is associated with decreased risk for recurrent wheezing among infants born to atopic parents. This effect was more pronounced in the subgroup of allergen‐sensitized infants.
cGMP Catabolism by Phosphodiesterase 5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism
Authors: Eiki Takimoto, Hunter C. Champion, Diego Belardi, Javid Moslehi, Marco Mongillo, Evanthia Mergia, David C. Montrose, Takayoshi Isoda, Kate Aufiero, Manuela Zaccolo, Wolfgang R. Dostmann, Carolyn J. Smith, David A. Kass
Journal: Circulation Research (2004)

Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by N(G)-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, showed no effect of PDE5A inhibition on beta-stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
Characterization of initiated cells in N-methylnitrosourea-induced carcinogenesis of the CNS in the adult rat
Authors: Demetrius M. Kokkinakis, Mark L. Watson, Lawrence S. Honig, Elisabeth J. Rushing, Bruce E. Mickey, S. Clifford Schold
Journal: Neuro-Oncology (2001)

Glial tumors may originate from the malignant transformation of multipotent glial progenitor cells, but tools to study malignant transformation leading to gliomas are limited by the lack of biological systems that represent early stages of this disease in adult animals. In order to characterize the initiated cells that give rise to gliomas, we have employed the N-methylnitrosourea (MNU) model for induction of brain tumors in adult rats (Rushing et al., 1998). Specifically, we have isolated and cultured transformed (premalignant) cells from normal-appearing brains of rats exposed to MNU for 10 weeks and from histologically abnormal brains of rats exposed to MNU for 15 weeks. We compared them with cells cultured from control animals under identical conditions. Cultured cells were classified according to their morphology, immunophenotype, karyotype, proliferation capacity, and tumorigenicity in athymic mice. Cultures from untreated normal rat brains grew as monolayers and had normal karyotypes (42 X,Y), epithelioid morphology, and slow proliferative capacity (doubling time > 120 h). In contrast, cultured cells from brains of MNU-exposed animals had karyotypes that ranged from normal to highly aneuploid. Aneuploid lines grew rapidly in multilayers (doubling time < 24 h), had differentiated astrocytic or oligodendroglial morphology and immunohistochemical staining profile, and yielded tumors in athymic mice. Initiated cells with minor chromosomal aberrations assumed mixed bipolar or tripolar morphologies in high density cultures, proliferated rapidly, but showed contact inhibition and failed to induce tumors when injected s.c. in athymic mice. In general, lines showing no evidence of chromosomal aberrations had the most epithelioid morphology, proliferated slowly (doubling time > 72 h), and retained strict contact growth inhibition. The presumed undifferentiated glial progenitor cells in culture from either control or MNU-treated rats variably expressed markers such as vimentin, nestin, and NG2 proteoglycan, and they weakly expressed the mature astrocytic or oligodendroglial markers glial fibrillary acidic protein or galactocerbroside, respectively. These cultures differentiated to bipolar-tripolar morphology with concomitant maturation to a GFAP+ or GalC+ phenotype upon exposure to secondary messengers such as dibutyryl-cyclic-AMP and/or growth factors such as basic fibrillary growth factor. Continuous stimulation with these messengers resulted in terminal differentiation and consequent death upon withdrawal of the stimulus. These results provide information that could lead to detailed characterization of initiated, premalignant cells in the adult brain and to a better understanding of glial carcinogenesis.
Serum Vitamin D Concentration Does Not Predict Insulin Action or Secretion in European Subjects With the Metabolic Syndrome
Authors: Hanne L. Gulseth, Ingrid M.F. Gjelstad, Audrey C. Tierney, Julie A. Lovegrove, Catherine Defoort, Ellen E. Blaak, Jose Lopez-Miranda, Beata Kiec-Wilk, Ulférus Ris, Helen M. Roche, Christian A. Drevon, Kåre I. Birkeland
Journal: Diabetes Care (2010)

OBJECTIVE To investigate the relation between serum concentration of 25-hydroxyvitamin D [25(OH)D] and insulin action and secretion. RESEARCH DESIGN AND METHODS In a cross-sectional study of 446 Pan-European subjects with the metabolic syndrome, insulin action and secretion were assessed by homeostasis model assessment (HOMA) indexes and intravenous glucose tolerance test to calculate acute insulin response, insulin sensitivity, and disposition index. Serum 25(OH)D was measured by high-performance liquid chromatography/mass spectrometry. RESULTS The 25(OH)D3 concentration was 57.1 ± 26.0 nmol/l (mean ± SD), and only 20% of the subjects had 25(OH)D3 levels ≥75 nmol/l. In multiple linear analyses, 25(OH)D3 concentrations were not associated with parameters of insulin action or secretion after adjustment for BMI and other covariates. CONCLUSIONS In a large sample of subjects with the metabolic syndrome, serum concentrations of 25(OH)D3 did not predict insulin action or secretion. Clear evidence that D vitamin status directly influences insulin secretion or action is still lacking.
Thymic hormone-containing cells. Characterization and localization of serum thymic factor in young mouse thymus studied by monoclonal antibodies.
Authors: W Savino, M Dardenne, M Papiernik, J F Bach
Journal: The Journal of Experimental Medicine (1982)

The characterization and distribution of cells containing the serum thymic factor (FTS) in the thymus of young mice was studied by immunofluorescence using monoclonal anti-FTS antibodies. FTS+ cells were distributed throughout the thymic parenchyma but were more frequent in the medullary region than in the cortex. FTS-containing cells presented a stellate or globular aspect, and some of them exhibited fluorescent cytoplasmic granules. The epithelial nature of FTS+ cells was confirmed by double-labeling experiments using an anti-keratin antiserum (as an epithelial cell marker). Nevertheless, only a minority of keratin-positive epithelial reticular cells contained FTS. All controls, including the incubation of sections from nonthymic tissues with the anti-FTS antibodies, were negative. Taken together, these results confirm the exclusive localization of FTS-containing cells within the mouse thymus.