tbuckley/cabot-search huggingface dataset:
Lower Respiratory Illnesses Promote FEV<sub>1</sub> Decline in Current Smokers But Not Ex-Smokers with Mild Chronic Obstructive Pulmonary Disease
Authors: RICHARD E. KANNER, NICHOLAS R. ANTHONISEN, JOHN E. CONNETT
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We analyzed Lung Health Study (LHS) data to assess the effect of self-reported lower respiratory illnesses resulting in physician visits (LRI) on lung function. Participants were 5,887 smokers aged 35–60 yr, FEV1/ FVC < 0.70 and FEV1 of 55–90% predicted. Two-thirds were randomized into an intensive smoking cessation program (SI); one-third were advised only to stop smoking (UC). For 5 yr participants had annual spirometry and questioning regarding LRI. SI had greater rates of smoking cessation than usual care (UC) with fewer LRI (p = 0.0008). Sustained quitters had fewer LRI than continuing smokers (p = 0.0003). In the year LRI occurred, FEV1 did not change in sustained quitters, but decreased significantly in smokers (p = 0.0001) with some recovery the following year if no LRI occurred. Over 5 yr, LRI had a significant effect on rate of decline of FEV1 only in smokers. In smokers averaging one LRI/yr over 5 yr there were additional declines in FEV1 of 7 ml /yr (p = 0.001). Smokers with more than one LRI / yr had greater declines. Chronic bronchitis was associated with increased frequencies of LRI, but did not affect their influence on lung function. Smoking and LRI had an interactive effect on FEV1 in people with mild COPD, and in smokers frequent LRI may influence the long-term course of the disease.Keywords: smoking; chronic obstructive pulmonary disease; lower respiratory infections; chronic bronchitis
S7 Evolution of lung function during the first two years of life in infants with cystic fibrosis diagnosed by newborn screening
Authors: L C Brennan, L P Thia, A Hoo, T Nguyen, J Chudleigh, S Lum, A Wade, C Wallis, A Bush, I Balfour-Lynn, H Wyatt, S Carr, J Stocks
Journal: Thorax (2013)

<h3>Background</h3> In contrast to findings from the Australian AREST-CF study1 infants with cystic fibrosis (CF) diagnosed by newborn screening (NBS) participating in the London CF Collaboration (LCFC) study2 were found to have relatively mild lung disease by 1 year of age when compared to healthy controls. <h3>Hypothesis</h3> In NBS CF infants, lung function remains stable to 2 years. <h3>Methods</h3> Lung clearance index (LCI), plethysmographic functional residual capacity (FRC) and forced expiratory volume (FEV<sub>0.5</sub>) from the raised volume technique were measured in NBS CF infants and healthy controls at 3months (3m), 1year (1y) and 2 years (2y). Results were expressed as z-scores using equipment-specific equations to adjust for age, sex and body size. <h3>Results</h3> To date, 55 CF and 28 control infants have been assessed on all 3 occasions. The mildly elevated LCI and FRC in CF infants identified by 3m when compared with controls remained stable thereafter. The significant reduction in FEV<sub>0.5 </sub>(mean difference (95% CI) -1.26 (-1.73; -0.79) z score) among CF infants at 3m had improved by 1y (see Figure 1). From 1 to 2 years all 3 measurements remained stable with no significant changes in average z-scores for either the CF or control infants. On average, LCI, FRC and FEV<sub>0.5</sub> only changed by 0.02, 0.16 and 0.06 z-scores respectively amongst CF children between 1 2 years, similar to that observed in controls. Mean (95%CI) group differences (CF-HC) in change of LCI, FRC and FEV<sub>0.5</sub>between 1 2y were 0.02 (-0.61; 0.66), p = 0.94;-0.05 (-0.61; 0.51), p = 0.86; and 0.32 (-0.27; 0.90) p = 0.29, respectively. <h3>Conclusions</h3> This is the first study to demonstrate stable lung function to 2y in NBS CF infants managed on standard CF therapy. These results suggest that in many of these infants novel treatments could be deferred beyond infancy when objective outcomes are more easily measured. <h3>References</h3> Pillarisetti <i><i>et al. AJRCCM</i></i> 2011 Hoo <i><i>et al Thorax</i></i> 2012.
Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia
Authors: Jan Dürig, Holger Nückel, Andreas Hüttmann, Elisabeth Kruse, Tanja Hölter, Katja Halfmeyer, Anja Führer, Roland Rudolph, Naser Kalhori, Arnd Nusch, Silvia Deaglio, Fabio Malavasi, Tarik Möröy, Ludger Klein-Hitpass, Ulrich Dührsen
Journal: Blood (2003)
Dying scientifically: sex and scandal in Victorian medicine
Authors: Sarah Chaney
Journal: The Lancet (2012)

In 1887, physician Edward Berdoe (under the pseudonym, "Aesculapius Scalpel") put pen to paper and scandalised the medical profession with his anonymous novel, St Bernard's: The Romance of a Medical Student. With its salacious cast of wife-poisoning vivisectionists and "villainous young hooligan" medical students, this gothic text was "a gross calumny upon medical students and their teachers; upon hospitals and their staffs" one Lancet reviewer complained. Such criticisms invariably focused on the medical setting, rather than the sketchy "romance" of the title.
IL-7 and IL-15 independently program the differentiation of intestinal CD3−NKp46+ cell subsets from Id2-dependent precursors
Authors: Naoko Satoh-Takayama, Sarah Lesjean-Pottier, Paulo Vieira, Shinichiro Sawa, Gerard Eberl, Christian A.J. Vosshenrich, James P. Di Santo
Journal: The Journal of Experimental Medicine (2010)

The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3−NKp46+ cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1+, Ly49+) but also a large CD127+NK1.1− subset of lymphoid tissue inducer (LTi)–like Rorc+ cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3−NKp46+ subsets. Gut CD3−NKp46+ cells were related to LTi and NK cells in requiring the transcriptional inhibitor Id2 for normal development. Overexpression of IL-15 in intestinal epithelial cells expanded NK1.1+ cells within the gut but had no effect on absolute numbers of the CD127+NK1.1−Rorc+ subset of CD3−NKp46+ cells. In contrast, IL-7 deficiency strongly reduced the overall numbers of CD3−NKp46+NK1.1− cells that express Rorc and produce IL-22 but failed to restrict homeostasis of classical intestinal NK1.1+ cells. Finally, in vivo fate-mapping experiments demonstrated that intestinal NK1.1+CD127− cells are not the progeny of Rorc-expressing progenitors, indicating that CD127+NK1.1−Rorc+ cells are not canonical NK cell precursors. These studies highlight the independent cytokine regulation of functionally diverse intestinal NKp46+ cell subsets.
The organization of human postural movements: A formal basis and experimental synthesis
Authors: Lewis M. Nashner, Gin McCollum
Journal: Behavioral and Brain Sciences (1985)

Abstract A scheme for understanding the organization of human postural movements is developed in the format of a position paper. The structural characteristics of the body and the geometry of muscular actions are incorporated into a three-dimensional graphical representation of human movement mechanics in the sagittal plane. A series of neural organizational hypotheses limit a theoretically infinite number of combinations of muscle contractions and associated movement trajectories for performing postural corrections: (1) Controls are organized to use the minimum number of muscles; (2) frequently performed movements are organized to require a minimum of neural decision-making. These hypotheses lead to the prediction that postural movements are composed of muscle contractile strategies derived from a limited set of distinct contractile patterns. The imposition of two mechanical constraints related to the configuration of support and to requirements for body stability with respect to gravity predict the conditions under which individual movement strategies will be deployed. A complementary organizational scheme for the senses is developed. We show that organization of postural movements into combinations of distinct strategies simplifies the interpretation of sensory inputs. The fine-tuning of movement strategies can be accomplished by breaking down the complex array of feedback information into a series of scalar quantities related to the parameters of the movement strategies. For example, the magnitude, aim, and curvature of the movement trajectory generated by an individual strategy can be adjusted independently. The second half of the report compares theoretical predictions with a series of actual experimental observations on normal subjects and patients with known sensory and motor disorders. Actual postural movements conform to theoretical predictions about the composition of individual movement strategies and the conditions under which each strategy is used. Observations on patients suggest how breakdowns in individual steps within the logical process of organization can lead to specific movement abnormalities. Discussion focuses on the areas needing further experimentation and on the implications of the proposed organizational scheme. We conclude that although our organizational scheme is not new in demonstrating the need for simplifying the neural control of movement, it is perhaps original in imposing discrete logical control upon a continuous mechanical system. The attraction of the scheme is that it provides a framework compatible with both mechanical and physiological information and amenable to experimental testing.
Nuclear Factor-κB Induction by Visfatin in Human Vascular Endothelial Cells
Authors: Raghu Adya, Bee K. Tan, Jing Chen, Harpal S. Randeva
Journal: Diabetes Care (2008)

Visfatin is elevated in obesity and type 2 diabetes and is thought to be an inflammatory mediator within atherosclerotic lesions and to induce gelatinase activity. We investigated the activation of nuclear factor-kappaB (NF-kappaB), a well-known proinflammatory transcription factor, by visfatin in endothelial cells.Human endothelial cells were transfected with pNF-kappaB-Luc plasmid. Using quantitative PCR, Western blot analysis, and gelatin zymography, we studied NF-kappaB signaling in gelatinase-mediated vascular inflammation by visfatin using the NF-kappaB inhibitor BAY 11-7085.Visfatin significantly increased NF-kappaB transcriptional activity (P < 0.001). We also found a significant inhibition of tumor necrosis factor-alpha (TNF-alpha)-induced NF-kappaB activity by visfatin (P < 0.001). Furthermore, the NF-kappaB inhibitor significantly negated visfatin-induced matrix metalloproteinase (MMP)-2/9 mRNA expression, protein levels, and gelatinolytic activity (P < 0.001).Visfatin-induced NF-kappaB signaling in human endothelial cells affects the activation of gelatinases MMP-2 and -9, suggesting an important role of visfatin in the pathogenesis of vascular inflammation in obesity and type 2 diabetes.
The Debate About Maintenance Is Not Over in Small-Cell Lung Cancer
Authors: Mehmet Artac, Hakan Bozcuk
Journal: Journal of Clinical Oncology (2007)

We read with interest the study of Arnold et al 1 about vandetanib as a maintenance therapy in patients with small-cell lung cancer (SCLC).They reported that maintenance therapy in SCLC with both chemotherapy and other agents did not affect the survival.However, a meta-analysis revealed the improvement of survival in SCLC with maintenance chemotherapy. 2 In this metaanalysis, maintenance chemotherapy improved 1-and 2-year overall survival by 9% (from 30% to 39%) and 4% (from 10% to 14%), respectively.Similarly, 1-and 2-year progression-free survival were also improved.Indeed, only a few randomized clinical trials reported so far (three of 14) have shown an overall survival difference in favor of maintenance chemotherapy.It is interesting that in two trials showing the superiority of maintenance chemotherapy, the induction therapy was cyclophosphamide, adriamycin, and vincristine, and the maintenance regimen was etoposide and cisplatin. 3,4 These two trials perhaps show that the inclusion of a less cross-resistant second-line chemotherapeutic regimen might improve the therapeutic efficacy of the whole strategy.Another issue about the study by Arnold et al 1 is that although this was a randomized trial, the patients receiving vandetanib were less likely to have received chemotherapy (28% v 32%) and radiation (34% v 43%) after progression.Could this have affected overall survival?In our opinion, this should be regarded as a confounding factor that could have diminished the survival in the vandetanib arm.In short, we believe the debate about the role of maintenance approaches in the management of SCLC is not over.Biologic agents and/or novel chemotherapeutic regimens should be tested in randomized trials in the maintenance setting.
Increased Cardiovascular Reactivity Caused by Depletion of Endogenous Renin in Dogs
Authors: RUBEN D. BUNAG, JAMES W. MCCUBBIN, IRVINE H. PAGE
Journal: Circulation Research (1968)

Increase in cardiovascular reactivity following bilateral nephrectomy has previously been found to be independent of the presence of the central nervous system, mechanical exclusion of the renal vascular bed, or loss of renal excretory function. It was considered possible that increased responsiveness results from removal of endogenous stores of renin. In nephrectomized dogs treated with crude kidney extracts, or infused continuously with synthetic angiotensin for 48 hours, enhancement of response to angiotensin and renin was inhibited while that to norepinephrine was not; response to tyramine was augmented as after infusion of angiotensin into intact dogs. Treatment with liver extracts alone did not inhibit response to renin or angiotensin; neither did continuous infusion of norepinephrine. When hog renin was added to liver extracts, the combination had the same inhibitory effect as kidney extracts. The data are in accord with the concept that depletion of endogenous renin contributes to the enhanced pressor responsiveness that occurs following bilateral nephrectomy.
Safety and efficacy of low-dose subcutaneous erythropoietin in hemodialysis patients.
Authors: K P Parker, W E Mitch, J C Stivelman, E J Macon, J L Bailey, J M Sands
Journal: Journal of the American Society of Nephrology (1997)

Anemia in hemodialysis patients is effectively treated by intravenous (IV) injections of recombinant human erythropoietin (rHuEPO) at each dialysis session. Because the hormone is effective by subcutaneous (SC) administration, it was decided that this study would evaluate low-dose weekly SC rHuEPO therapy. To determine the safety and efficacy of weekly SC rHuEPO administration to hemodialysis patients, only one third the weekly IV dose was given and the effects were compared with those from an age-, gender-, and nephrologic disease-matched control group treated in the standard fashion. Forty-four patients entered the trial and 27 completed the protocol along with 27 control subjects. During Phase 1, experimental and control subjects received standard IV rHuEPO at dialysis for 6 months. During Phase 2, experimental patients received weekly SC rHuEPO at one third the weekly IV dose for 10 months; control subjects continued to receive IV therapy. In Phase 3, both groups were treated for 6 more months with IV rHuEPO. In Phase 2, there was no significant reduction in hematocrit value, reticulocyte count, transferrin saturation, or ferritin level in the experimental group, even with only one third the weekly rHuEPO IV dose over the 10-month period. There were no significant differences between IV and SC rHuEPO administration or between experimental and control subjects in blood pressure, serum chemistries, or parameters of "dialysis adequacy." It was concluded that low-dose weekly SC rHuEPO administration is a safe and effective method for maintaining the hematocrit level of stable hemodialysis patients. This therapy could enhance the efficacy of rHuEPO and substantially reduce costs while preserving patient care outcomes.
Basolateral transport of tetraethylammonium by a clone of LLC-PK1 cells.
Authors: T D McKinney, M B Scheller, M Hosford, M E Lesniak, T S Haseley
Journal: Journal of the American Society of Nephrology (1992)

In these studies, a clone of cells derived from the porcine renal epithelial line LLC-PK1 grown on porous filters was used to evaluate basolateral uptake of the organic cation tetraethylammonium (TEA). (3H) TEA (1 microM) entered cells in a saturable and time-dependent manner achieving a steady-state value at 2 to 2.5 h. Uptake was reduced by hypothermia and the metabolic inhibitors sodium azide and iodoacetate. Several other organic cations in 1 mM concentrations inhibited the majority of TEA uptake. In lower concentrations, the inhibitory potency of these was: verapamil greater than cimetidine approximately amiloride approximately quinidine greater than procainamide approximately N1-methylnicotinamide. When sodium was replaced with potassium in the uptake medium, TEA uptake was also reduced consistent with electrogenic transport. However, uptake was reduced further by 1 mM cimetidine in the presence of both NaCl and KCl buffers. TEA uptake was not significantly different when the media pH was varied from 6.0 to 8.0. In addition, results of experiments in which intracellular pH was altered with NH4Cl were not consistent with the presence of organic cation/proton exchange. TEA/TEA exchange could not be demonstrated in experiments in which cells were preloaded with 1 mM nonradioactive TEA and uptake of (3H)TEA was measured or in which nonradioactive TEA in the external medium failed to enhance efflux from cells preloaded with (3H)TEA. These results indicate that the basolateral membrane of LLC-PKc10 cells has one or more transport processes for the mediated uptake of organic cations. However, the precise mechanism(s) involved in this transport remains to be elucidated.
Neuropeptides of the autonomic nervous system in Sjogren's syndrome
Authors: N. Santavirta, Y. T Konttinen, J. Tornwall, M. Segerberg, S. Santavirta, M. Matucci-Cerinic, H. Bjorvell
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To assess the activity level of the autonomic nervous system in Sjögren's syndrome (SS) and to correlate this with stress. <h3>METHODS</h3> Patients with SS (n=12) and healthy controls (n=10) were analysed for the content of vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) in their stimulated saliva by radioimmunoassays and for stress by the use of a modified Jenkins Activity Survey (JAS). <h3>RESULTS</h3> The data are expressed as median (interquartile range). Salivary VIP output (pg/min) and NPY output (pg/min) were high in SS compared with healthy controls (30.0 (15.6, 36.6) versus 12.3 (9.2, 24.0), p=0.045, 4.8 (0.6, 24.1) versus 0.7 (0.0, 2.4), p=0.038, respectively). Patients experienced only a little, but not significantly, more stress than the healthy controls (stress index −2.8 (−7.7, 6.9) versus −5.2 (−12.9, 2.7), p&gt;0.05). Stress in general was associated with high salivary VIP concentrations (<i>r</i>=0.41, p=0.05). <h3>CONCLUSIONS</h3> These findings show that adequately processed saliva (containing aprotinin and EDTA as neuropeptidase inhibitors) contains measurable amounts of marker peptides of the autonomic nervous system. Secondly, VIP concentration but not output may be affected by stress, which may act by decreasing watery salivary flow. In patients with SS, VIP and NPY outputs are increased. This may indicate increased leakage into saliva or efforts to compensate for the diminished salivary flow, or both.
Integration of Metabolomics and Transcriptomics Revealed a Fatty Acid Network Exerting Growth Inhibitory Effects in Human Pancreatic Cancer
Authors: Geng Zhang, Peijun He, Hanson Tan, Anuradha Budhu, Jochen Gaedcke, B. Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Anirban Maitra, Nader Hanna, H. Richard Alexander, S. Perwez Hussain
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To identify metabolic pathways that are perturbed in pancreatic ductal adenocarcinoma (PDAC), we investigated gene-metabolite networks with integration of metabolomics and transcriptomics. Experimental Design: We conducted global metabolite profiling analysis on two independent cohorts of resected PDAC cases to identify critical metabolites alteration that may contribute to the progression of pancreatic cancer. We then searched for gene surrogates that were significantly correlated with the key metabolites, by integrating metabolite and gene expression profiles. Results: Fifty-five metabolites were consistently altered in tumors as compared with adjacent nontumor tissues in a test cohort (N = 33) and an independent validation cohort (N = 31). Weighted network analysis revealed a unique set of free fatty acids (FFA) that were highly coregulated and decreased in PDAC. Pathway analysis of 157 differentially expressed gene surrogates revealed a significantly altered lipid metabolism network, including key lipolytic enzymes PNLIP, CLPS, PNLIPRP1, and PNLIPRP2. Gene expressions of these lipases were significantly decreased in pancreatic tumors as compared with nontumor tissues, leading to reduced FFAs. More importantly, a lower gene expression of PNLIP in tumors was associated with poorer survival in two independent cohorts. We further showed that two saturated FFAs, palmitate and stearate, significantly induced TRAIL expression, triggered apoptosis, and inhibited proliferation in pancreatic cancer cells. Conclusions: Our results suggest that impairment in a lipolytic pathway involving lipases, and a unique set of FFAs, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. Clin Cancer Res; 19(18); 4983–93. ©2013 AACR.
What makes CRCs metastasise?
Authors: G. A. Meijer
Journal: Gut (2010)

Colorectal cancer arises from normal epithelial cells lining the large intestine. Turning normal epithelial cells into cancer cells requires extensive reprogramming of their biological properties in order to make them survive as tumour cells, an evolutionary process driven by changes at the (epi)genetic level. Concepts from tumour biology teach that the processes involved include increased proliferation, evasion of apoptosis, disruption of cell cycle check points, disruption of basal membrane, cell motility, remodelling of the extra-cellular matrix and recruiting new stroma, including angiogenesis, and on top of this, escape from the immune system. Basically, tumour cells need to be proficient in these processes for producing both a primary invasive cancer and metastatic outgrowths.

Two hypotheses exist as to how tumour cells acquire the (epi)genomic programmes that determine their ultimate fate; that is, whether or not metastasis will occur. According to one model, tumour cells sequentially first acquire the (epi)genetic alterations that render them premalignant lesions; next, alterations occur that are necessary to become invasive; and thereafter, when a primary cancer has already become fully established, cells would acquire by further stochastic mutations the properties necessary to produce metastasis. …
A missense mutation in the heavy subunit of γ-glutamylcysteine synthetase gene causes hemolytic anemia
Authors: Ellinor Ristoff, Camilla Augustson, Judy Geissler, Thea de Rijk, Katarina Carlsson, Jia-Li Luo, Kerstin Andersson, Ron S. Weening, Rob van Zwieten, Agne Larsson, Dirk Roos
Journal: Blood (2000)