tbuckley/cabot-search huggingface dataset:
Appropriate, Timely Referral to Palliative Care Services: A Name Change Will Not Help
Authors: Donna Milne, Michael Jefford, Penelope Schofield, Sanchia Aranda
Journal: Journal of Clinical Oncology (2013)

Milne et al 1 contend that changing the name "palliative care" to "supportive care" would not change referral practices to palliative care services and that education of patients and caregivers, as well as physicians, is essential.They support this argument with data from a qualitative study, in which they interviewed patients, family caregivers, and health professionals.Our survey 2 was not designed to address the question of whether or not palliative care should be renamed, and we therefore did not come to any conclusions
RISK OF HTLV INFECTION IN PATIENTS ON HAEMODIALYSIS
Authors: Kohichi Shimase, Hiroshi Ichimura, Ikuo Tamura, Eiji Kaneto, Osamu Kurimura, Koji Nanba, Norihiko Hino, Tetsuya Ono, Jun Kawai, Takahisa Takasugi, Hirokuni Taguchi, Masatoshi Fujishita, Isao Miyoshi, Naotami Terao, Eiichi Shimazu
Journal: The Lancet (1984)
Microfluidic Technologies for Temporal Perturbations of Chemotaxis
Authors: Daniel Irimia
Journal: Annual Review of Biomedical Engineering (2010)

Most cells in the body have the ability to change their physical locations during physiologic or pathologic events such as inflammation, wound healing, or cancer. When cell migration is directed toward sources of cue chemicals, the process is known as chemotaxis, and it requires linking the sensing of chemicals through receptors on the surfaces of the cells to the directional activation of the motility apparatus inside the cells. This link is supported by complex intracellular signaling pathways, and although details regarding the nature of the molecules involved in the signal transduction are well established, far less is known about how different signaling molecules and processes are dynamically interconnected and how slower and faster signaling events take place simultaneously inside moving cells. In this context, advances in microfluidic technologies are enabling the emergence of new tools that facilitate the development of experimental protocols in which the cellular microenvironment is precisely controlled in time and space and in which signaling-associated changes inside cells can be quantitatively measured and compared. These tools could enable new insights into the intricacies of the biological systems that participate in chemotaxis processes and could have the potential to accelerate the development of novel therapeutic strategies to control cell motility and enhance our abilities for medical intervention during health and disease.
Genetic essential tremor in γ-aminobutyric acidA receptor α1 subunit knockout mice
Authors: Jason E. Kralic, Hugh E. Criswell, Jessica L. Osterman, Todd K. O’Buckley, Mary E. Wilkie, Douglas B. Matthews, Kristin Hamre, George R. Breese, Gregg E. Homanics, A. Leslie Morrow
Journal: Journal of Clinical Investigation (2005)

Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acidA (GABAA) receptor α1–/– mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethanol; the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801; the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the GABAA receptor modulators diazepam, allopregnanolone, and Ro15-4513; and the L-type Ca2+ channel antagonist nitrendipine. Primidone, propranolol, and gabapentin reduced the amplitude (power) of the pathologic tremor. Nonsedative doses of ethanol eliminated tremor in mice. Diazepam, allopregnanolone, Ro15-4513, and nitrendipine had no effect or enhanced tremor, whereas MK-801 and CCPA reduced tremor. To understand the etiology of tremor in these mice, we studied the electrophysiological properties of cerebellar Purkinje cells. Cerebellar Purkinje cells in GABAA receptor α1–/– mice exhibited a profound loss of all responses to synaptic or exogenous GABA, but no differences in abundance, gross morphology, or spontaneous synaptic activity were observed. This genetic animal model elucidates a mechanism of GABAergic dysfunction in the major motor pathway and potential targets for pharmacotherapy of essential tremor.
Oxytocin—its role in male reproduction and new potential therapeutic uses
Authors: Hemlata Thackare, Helen D. Nicholson, Kate Whittington
Journal: Human Reproduction Update (2006)

Oxytocin (OT) is traditionally thought of as a ‘female’ neurohypophysis hormone due to its role in parturition and milk ejection. However, OT is recognized as having endocrine and paracrine roles in male reproduction. At ejaculation, a burst of OT is released from the neurohypophysis into the systemic circulation and stimulates contractions of the reproductive tract aiding sperm release. There is conclusive evidence that OT is synthesized within the mammalian testis, epididymis and prostate and the presence of OT receptors (OTRs) through the reproductive tract supports a local action for this peptide. OT has a paracrine role in stimulating contractility of the seminiferous tubules, epididymis and the prostate gland. Interestingly, OT has also been shown to modulate androgen levels in these tissues via stimulation of the conversion of testosterone to dihydrotestostone (DHT) by 5α-reductase. The elucidation of OT’s role in male reproduction has suggested a number of potential therapeutic uses for this hormone. Exogenous administration of OT has, in some cases, been shown to increase the numbers of ejaculated sperm, possibly by stimulating contractions of the reproductive tract and thus aiding sperm passage. Within the prostate, OT has been shown to affect gland growth both directly and via its interaction with androgen metabolism. Prostate pathologies due to unregulated cell proliferation/growth, such as benign prostatic hyperplasia and cancer, are unfortunately very common and few effective treatments are available. Greater understanding of paracrine growth mediators, such as OT, is likely to provide new mechanisms for treating such pathologies.
Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study
Authors: N. B. Klarenbeek, S. M. van der Kooij, M. Guler-Yuksel, J. H. L. M. van Groenendael, K. H. Han, P. J. S. M. Kerstens, T. W. J. Huizinga, B. A. C. Dijkmans, C. F. Allaart
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis (RA) in sustained clinical remission, to identify predictors of a relapse and to evaluate treatment response after restarting treatment. <h3>Methods</h3> Five-year data from the BeSt study were used, in which 508 patients with recent-onset RA were randomised into four dynamic treatment strategies, aiming at a disease activity score (DAS) ≤2.4. When DAS was &lt;1.6 for ≥6 months, the last disease-modifying antirheumatic drug (DMARD) was tapered and discontinued. If DAS increased to ≥1.6, the last DMARD was immediately reintroduced. <h3>Results</h3> During a 5-year period, 115/508 patients (23%) achieved drug-free remission. Of these, 53 patients (46%) restarted treatment because the DAS was ≥1.6 after a median of 5 months, 59 patients (51%) remained in drug-free remission for a median duration of 23 months and 3 (3%) were lost to follow-up. In those who restarted treatment, mean (SD) DAS increased from 1.13 (0.73) at remission before tapering to 2.18 (0.65) at restart, reflecting an increase in all four components of DAS. Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide (anti-CCP), last DMARD sulfasalazine, low baseline Health Assessment Questionnaire score and high mean DAS until remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3–6 months after the restart. The median (IQR) damage progression in those who restarted treatment during the year of DAS increase was 0 (0–1) Sharp-van der Heijde units. <h3>Conclusion</h3> During 5 years DAS steered treatment, nearly 25% of patients with RA achieved drug-free remission; 46% restarted DMARD monotherapy because of a relapse, the majority of whom again achieved clinical remission within 3–6 months without showing radiological progression during the relapse.
Relative Potencies of 1,25-(OH)2D3 and 19-Nor-1,25-(OH)2D2 on Inducing Differentiation and Markers of Bone Formation in MG-63 Cells
Authors: JANE L. FINCH, ADRIANA S. DUSSO, TRICIA PAVLOPOULOS, EDUARDO A. SLATOPOLSKY
Journal: Journal of the American Society of Nephrology (2001)

19-Nor-1,25-(OH)(2)D(2), an analog of 1,25-(OH)(2)D(3), is used to treat secondary hyperparathyroidism because it suppresses parathyroid hormone synthesis and secretion with lower calcemic and phosphatemic activities. 19-Nor-1,25-(OH)(2)D(2) is approximately 10 times less active than 1,25-(OH)(2)D(3) in promoting bone resorption, which accounts in part for the low potency of this analog in increasing serum calcium and phosphorus. Concern that 19-nor-1,25-(OH)(2)D(2) also could be less potent than 1,25-(OH)(2)D(3) on bone formation led to a comparison of the potency of both compounds on osteoblasts. In the human osteoblast-like cell line MG-63, 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) had a similar potency in upregulating vitamin D receptor content and suppressing proliferation. Both sterols caused a similar reduction in DNA content and proliferating cell nuclear antigen protein expression. Time-course and dose-response studies on 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) induction of the marker of bone formation, osteocalcin, showed overlapping curves. The effects on alkaline phosphatase (ALP) activity also were studied in MG-63 cells that had been co-treated with either sterol and transforming growth factor-beta, an enhancer of 1,25-(OH)(2)D(3)-induced ALP activity in this cell line. Transforming growth factor-beta alone had no effect, whereas 1,25-(OH)(2)D(3) and 19-nor-1,25-(OH)(2)D(2) increased ALP activity similarly. These studies demonstrate that 19-nor-1,25-(OH)(2)D(2) has the same potency as 1,25-(OH)(2)D(3) not only in inducing vitamin D receptor content, osteocalcin levels, and ALP activity but also in controlling osteoblastic growth. Therefore, it is unlikely that 19-nor-1,25-(OH)(2)D(2) would have deleterious effects on bone remodeling.
High-dose treatment with autologous bone marrow support as consolidation of first remission in younger patients with acute myelogenous leukaemia
Authors: A.Z.S. Rohatiner, R. Bassan, R. Raimondi, J.A.L. Amess, S. Arnott, A. Personen, F. Rodeghiero, T. Barbui, M.J. Bradburn, M. Carter, T.A. Lister
Journal: Annals of Oncology (2000)
No evidence for neural filling-in – vision as an illusion – pinning down “enaction”
Authors: J. K. O'Regan
Journal: Behavioral and Brain Sciences (1998)

(1) The purported evidence for neural filling-in is not evidence for filling-in, but just for long-range dynamic interactions. (2) Vision is perhaps not an “illusion,” but at any rate it is not “pictorial.” (3) The idea of the “world as an outside memory” as well as MacKay's “conditional readiness for action” may help approach an “enactive” theory of vision.
A STUDY OF THE CHANGES IN VIRULENCE OF THE PNEUMOCOCCUS AT DIFFERENT PERIODS OF GROWTH AND UNDER DIFFERENT CONDITIONS OF CULTIVATION IN MEDIA
Authors: Augustus B. Wadsworth, Mary Butler Kirkbride
Journal: The Journal of Experimental Medicine (1918)

It has been possible by rapid transfers alone, not only to maintain the virulence for mice of the pneumococcus in artificial media but also to restore a certain degree of virulence to cultures previously rendered non-virulent by less rapid transfers in the same medium. For these results the presence of enriching fluids such as blood or serum is not required. In addition it has been shown that attenuated cultures, which had been repeatedly demonstrated to be avirulent for mice at the 24 hour period of growth, exhibited marked pathogenicity if injected during, or especially at the commencement of the period of maximum growth when the growth energy may be considered at its height. In these cultures, however, the increase in virulence was usually less than in others transferred repeatedly at frequent intervals. The significance of these results is not necessarily limited to pneumococcus infections. Other lines of investigation are suggested which may possibly help to clarify certain conceptions of the relation which the different activities of the bacterial cell as an agent of infection bear to one another and to the host in various infectious diseases. Although the pneumococcus may offer an especially striking example for purposes of demonstration by experiment, it is not probable that the close relation between the vegetative power or growth energy of the pneumococcus and its pathogenic power is peculiar to this organism. The vegetative power may depend upon many conditions affecting both the host and the bacterial agent of infection. Different species of bacteria may acquire or develop it in different degrees under different conditions. But it must assuredly form the basis not only of the essentially parasitic but also of the more special toxicogenic activities of the bacteria.
Plasma Gelsolin and Circulating Actin Correlate with Hemodialysis Mortality
Authors: Po-Shun Lee, Kartik Sampath, S. Ananth Karumanchi, Hector Tamez, Ishir Bhan, Tamara Isakova, Orlando M. Gutierrez, Myles Wolf, Yuchiao Chang, Thomas P. Stossel, Ravi Thadhani
Journal: Journal of the American Society of Nephrology (2009)

Plasma gelsolin (pGSN) binds actin and bioactive mediators to localize inflammation. Low pGSN correlates with adverse outcomes in acute injury, whereas administration of recombinant pGSN reduces mortality in experimental sepsis. We found that mean pGSN levels of 150 patients randomly selected from 10,044 starting chronic hemodialysis were 140 ± 42 mg/L, 30 to 50% lower than levels reported for healthy individuals. In a larger sample, we performed a case-control analysis to evaluate the relationship of pGSN and circulating actin with mortality; pGSN levels were significantly lower in 114 patients who died within 1 yr of dialysis initiation than in 109 survivors (117 ± 38 mg/L versus 147 ± 42 mg/L, P < 0.001). pGSN levels had a graded, inverse relationship with 1-yr mortality, such that patients with pGSN <130 mg/L experienced a >3-fold risk for mortality compared with those with pGSN ≥150 mg/L. The 69% of patients with detectable circulating actin had lower pGSN levels than those without (127 ± 45 mg/L versus 141 ± 36 mg/L, P = 0.026). Compared with patients who had elevated pGSN and no detectable actin, those with low pGSN levels and detectable actin had markedly increased mortality (odds ratio 9.8, 95% confidence interval 2.9 to 33.5). Worsening renal function correlated with pGSN decline in 53 subjects with CKD not on dialysis. In summary, low pGSN and detectable circulating actin identify chronic hemodialysis patients at highest risk for 1-yr mortality.
Calcium release from the sarcoplasmic reticulum.
Authors: A Fabiato, F Fabiato
Journal: Circulation Research (1977)

Calcium that induces contraction by interacting with the contractile proteins of muscle cells may be derived from different sources: extracellular space including the basement membrane, sarcoplasmic reticulum (SR) and, under certain circumstances, mitochondria. 1" 3 Among these sources of Ca 2+ for excitation-contraction coupling the contribution of the SR varies between different types of muscles: cardiac, skeletal, and smooth. 1 ' 4 ~<i An unresolved question concerns the nature of these variations: Are they only quantitative or also qualitative, consisting of fundamentally different mechanisms for the release of Ca 2+ from the SR?This review tries to answer that question.The greatest attention is placed on the mechanism of Ca 2+ release from the SR of cardiac muscle and this is compared to release in skeletal muscle.Not much space is devoted to smooth muscle, simply because little is known of the mechanisms of Ca 2+ release from the SR in this tissue.Studies concerning the sources of Ca 2+ other than the SR 1 " 3 and the mechanisms of Ca 2+ transport by the SR which are not directly related to the release processes will not be discussed.The first event in excitation-contraction coupling is the action potential.It is generally admitted that some Ca 2+ crosses the surface membrane of the cardiac cell during the action potential, whereas little or no Ca 2+ crosses the surface membrane of skeletal muscle cells. 1 " 5 Two processes have been proposed as possible links between the action potential of the sarcolemma and the release of Ca 2+ from the SR: the Ca 2+ -induced release of Ca 2+ and the "depolarization-induced" release of Ca 2+ :Ca 2+ -Induced Release of Ca 2+ .According to this hypothesis, the small amount of Ca 2+ that crosses the sarcolemma during the action potential is insufficient by itself to activate the myofilaments but induces a release of Ca 2+ from the SR sufficient for activation. 7" 16 "Depolarization-Induced" Release of Ca 2+ .According to this hypothesis, the action potential traveling in the transverse tubules induces a modification of the SR membrane that increases its permeability to Ca 2+ and thereby results in a release of Ca 2+ from the SR. 17 " 21 However, it is
Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns
Authors: Joachim Weischenfeldt, Johannes Waage, Geng Tian, Jing Zhao, Inge Damgaard, Janus Schou Jakobsen, Karsten Kristiansen, Anders Krogh, Jun Wang, Bo T Porse
Journal: Genome biology (2012)

Nonsense-mediated mRNA decay (NMD) affects the outcome of alternative splicing by degrading mRNA isoforms with premature termination codons. Splicing regulators constitute important NMD targets; however, the extent to which loss of NMD causes extensive deregulation of alternative splicing has not previously been assayed in a global, unbiased manner. Here, we combine mouse genetics and RNA-seq to provide the first in vivo analysis of the global impact of NMD on splicing patterns in two primary mouse tissues ablated for the NMD factor UPF2.We developed a bioinformatic pipeline that maps RNA-seq data to a combinatorial exon database, predicts NMD-susceptibility for mRNA isoforms and calculates the distribution of major splice isoform classes. We present a catalog of NMD-regulated alternative splicing events, showing that isoforms of 30% of all expressed genes are upregulated in NMD-deficient cells and that NMD targets all major splicing classes. Importantly, NMD-dependent effects are not restricted to premature termination codon+ isoforms but also involve an abundance of splicing events that do not generate premature termination codons. Supporting their functional importance, the latter events are associated with high intronic conservation.Our data demonstrate that NMD regulates alternative splicing outcomes through an intricate web of splicing regulators and that its loss leads to the deregulation of a panoply of splicing events, providing novel insights into its role in core- and tissue-specific regulation of gene expression. Thus, our study extends the importance of NMD from an mRNA quality pathway to a regulator of several layers of gene expression.
Nitrite Therapy Improves Left Ventricular Function During Heart Failure via Restoration of Nitric Oxide–Mediated Cytoprotective Signaling
Authors: Shashi Bhushan, Kazuhisa Kondo, David J. Polhemus, Hiroyuki Otsuka, Chad K. Nicholson, Ya-Xiong Tao, Hui Huang, Vasiliki V. Georgiopoulou, Toyoaki Murohara, John W. Calvert, Javed Butler, David J. Lefer
Journal: Circulation Research (2014)

Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
Long-Term Complications and Mortality in Young-Onset Diabetes
Authors: Maria I. Constantino, Lynda Molyneaux, Franziska Limacher-Gisler, Abdulghani Al-Saeed, Connie Luo, Ted Wu, Stephen M. Twigg, Dennis K. Yue, Jencia Wong
Journal: Diabetes Care (2013)

OBJECTIVE To evaluate long-term clinical outcomes and survival in young-onset type 2 diabetes (T2DM) compared with type 1 diabetes (T1DM) with a similar age of onset. RESEARCH DESIGN AND METHODS Records from the Royal Prince Alfred Hospital Diabetes Clinical Database, established in 1986, were matched with the Australian National Death Index to establish mortality outcomes for all subjects until June 2011. Clinical and mortality outcomes in 354 patients with T2DM, age of onset between 15 and 30 years (T2DM15–30), were compared with T1DM in several ways but primarily with 470 patients with T1DM with a similar age of onset (T1DM15–30) to minimize the confounding effect of age on outcome. RESULTS For a median observation period of 21.4 (interquartile range 14–30.7) and 23.4 (15.7–32.4) years for the T2DM and T1DM cohorts, respectively, 71 of 824 patients (8.6%) died. A significant mortality excess was noted in T2DM15–30 (11 vs. 6.8%, P = 0.03), with an increased hazard for death (hazard ratio 2.0 [95% CI 1.2–3.2], P = 0.003). Death for T2DM15–30 occurred after a significantly shorter disease duration (26.9 [18.1–36.0] vs. 36.5 [24.4–45.4] years, P = 0.01) and at a relatively young age. There were more cardiovascular deaths in T2DM15–30 (50 vs. 30%, P &amp;lt; 0.05). Despite equivalent glycemic control and shorter disease duration, the prevalence of albuminuria and less favorable cardiovascular risk factors were greater in the T2DM15–30 cohort, even soon after diabetes onset. Neuropathy scores and macrovascular complications were also increased in T2DM15–30 (P &amp;lt; 0.0001). CONCLUSIONS Young-onset T2DM is the more lethal phenotype of diabetes and is associated with a greater mortality, more diabetes complications, and unfavorable cardiovascular disease risk factors when compared with T1DM.