tbuckley/cabot-search huggingface dataset:
Twenty-Four-Hour Variations in DNA Synthesis of a Fast-Growing and a Slow-Growing Hepatoma: DNA Synthesis Rhythm in Hepatoma&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: R E Nash, J M Llanos
Journal: JNCI Journal of the National Cancer Institute (1971)

Twenty-four-hour variations in the DNA synthesis index, controlled by autoradiography after tritiated thymidine administration, are described in a slow-growing, differentiated hepatoma (SS1H) and in a fast-growing, undifferentiated hepatoma (SS1K) of mice. In hepatoma SS1H, these variations were circadian and reached a highly significant peak at 4 AM through 8 PM. In Hepatoma SS1K, these variations were only insignificant oscillations. The circadian variations in DNA synthesis of Hepatoma SS1H were correlated with those previously reported in mitotic activity of Hepatoma SS1H.
Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar
Authors: C. Horne, P.J.E. Quintana, P.A. Keown, H Dimich-Ward, M Chan-Yeung
Journal: European Respiratory Journal (2000)

Occupational asthma caused by western red cedar is a common problem in sawmill industries. The objective of this study was to examine a possible association of human leukocyte antigen (HLA) class II genetic markers with susceptibility or resistance to western red cedar induced asthma. The distribution of DRB1 and DQB1 HLA class II alleles and DRB1-DQB1 haplotypes was studied in 56 Caucasian patients with proven red cedar asthma and 63 healthy Caucasian control subjects exposed to red cedar dust. DRB1 and DQB1 high resolution typing was performed by the polymerase chain reaction-based method. Patients with red cedar asthma had a higher frequency of HLA DQB1*0603 and DQB1*0302 alleles compared to a group of healthy exposed control subjects and a reduced frequency of DQB1*0501 allele. The frequency of the DRB1*0401-DQB1* 0302 haplotype was increased and the DRB1*0101-DQB1*0501 haplotype was reduced. These findings suggest that genetic factors such as human leukocyte antigen class II antigens may be associated with susceptibility or resistance to development of red cedar asthma.
Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis
Authors: N. Schmidt, E. Gonzalez, A. Visekruna, A. A. Kuhl, C. Loddenkemper, H. Mollenkopf, S. H. E. Kaufmann, U. Steinhoff, T. Joeris
Journal: Gut (2010)

<h3>Background and aims</h3> Inflammatory bowel disease (IBD), comprising Crohn´s disease and ulcerative colitis, is characterised by chronic relapsing inflammation of the gut. Increased proteasome activity, associated with the expression of immunoproteasomes, was found to enhance proinflammatory signalling and thus promotes inflammation in patients with IBD. The aim of this study was to explore whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. <h3>Methods</h3> This concept was assessed in two different experimental set-ups. Development of dextran sodium sulfate (DSS)-induced colitis was tested (1) in <i>lmp7</i><sup>−/−</sup> mice lacking the immunoproteasome subunit LMP7 and (2) in wild-type (WT) mice treated with the proteasome inhibitor bortezomib. <h3>Results</h3> Compared with WT mice, <i>lmp7</i><sup>−/−</sup> mice develop significantly attenuated colitis due to reduced nuclear factor-κB (NF-κB) signalling in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches modulation of the proteasome activity limited the secretion of proinflammatory cytokines and chemokines. Consequently, infiltration of the colon by neutrophils and expansion of inflammatory T helper 1 (Th1) and Th17 T cells was diminished and thus prevented excessive tissue damage. <h3>Conclusions</h3> It was demonstrated that modulation of the proteasome activity is effective in attenuating experimental colitis. The results reveal that reduction of the proteasome activity either by partial inhibition with bortezomib or by specifically targeting the immunoproteasome subunit LMP7 is a suitable treatment of intestinal inflammation.
Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo
Authors: X Cheng
Journal: Cardiovascular Research (1999)

Objective: Although studies in vitro have implicated oxygen-derived free radicals as possible mediators of inflammatory cytokine-induced cell injury, the role of the radicals in the cytokine-induced myocardial dysfunction in vivo remains unclear. The present study was designed to address this point in our novel canine model of cytokine-induced myocardial dysfunction in vivo. Methods: Studies were performed in mongrel dogs, in which microspheres (MS, 15 μm in diameter) with and without interleukin-1β (IL-1β) were injected into the left main coronary artery (control and IL-1β group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week. Results: Immediately after the intracoronary injection of MS (106/kg), LVEF equally decreased to approximately 30% in both the control and IL-1β group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1β group until day 7 (p<0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg IV) and 1 and 2 days after IL-1β MS application (1 mg/kg IV) prevented the IL-1β-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1β group than in the control group at day 2 (p<0.01), and OPC-6535 significantly suppressed the IL-1β-induced superoxide production (p<0.01). An HPLC assay showed that nitrotyrosine, a marker of the formation of peroxynitrite by superoxide anion and nitric oxide, was present in the myocardium treated with IL-1β but not in that with control MS. OPC-6535 abolished the IL-1β-induced formation of myocardial nitrotyrosine. Conclusion: These results indicate that superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in dogs in vivo.
Trandolapril Reduces the Incidence of Atrial Fibrillation After Acute Myocardial Infarction in Patients With Left Ventricular Dysfunction
Authors: Ole Dyg Pedersen, Henning Bagger, Lars Køber, Christian Torp-Pedersen
Journal: Circulation (1999)

Background —Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown. Methods and Results —We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively, P &lt;0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P &lt;0.01). Conclusions —The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.
Tachyphylaxis to Alpha- and Beta-Angiotensin in Dogs Perfused with Ringer's Solution or Blood
Authors: WILLIAM J. LOUIS, GEORGE JERUMS
Journal: Circulation Research (1968)

Repeated injections of µ-asparaginyl-angiotensin in the hindquarters of dogs perfused either with blood or with Ringer's solution did not lead to tachyphylaxis with doses of less than 0.5 µg. Above this dose tachyphylaxis developed in preparations perfused with Ringer's solution. Tachyphylaxis occurred in blood-perfused preparations at doses of 2 µg and above. Tachyphylaxis to β-aspartyl-angiotensin appeared with doses above 0.5 µg irrespective of the perfusing medium used. It is concluded that plasma angiotensinase activity plays some part in limiting the development of techyphylaxis only to µ-asparaginyl-angiotensin; also, that removal of angiotensin from the biophase is dependent in part on the angiotensin being removed by perfusion. A dynamic model for the action of angiotensin on its receptor is proposed.
Mechanisms of Lymphocyte Activation
Authors: Guy B. Faguet
Journal: Journal of Clinical Investigation (1979)

Binding of (125)I-leukoagglutinin (LPHA) to lymphocyte membrane receptors at equilibrium generated similar curvilinear Scatchard plots in 20 patients with bursa-derived (B)-cell-type chronic lymphatic leukemia (CLL) and 15 controls. If biphasic plots are assumed, the two linear components show markedly diminished receptor capacity (15 and 137 ng/10(6) lymphocytes) in CLL as compared to controls (60 and 668 ng). In contrast, affinity was similar in patients (1.0 x 10(8) M(-1) and 2.1 x 10(6) M(-1)) and controls (1.8 x 10(8) M(-1) and 1.5 x 10(6) M(-1)). Highly purified B cells from patients and controls generated binding data comparable to that obtained from the mixed lymphocyte (ML) suspensions from which they originated. Maximal DNA synthesis of highly purified, normal, thymus-derived (T) and B cells in response to LPHA stimulation was comparable to that of ML (mitotic index [MI] 19.9, 20.1, and 23.4, respectively), though B-cell responses were slightly delayed. In CLL the markedly decreased and delayed DNA synthesis by ML (MI 2.3), and by highly purified T (MI 1.6) and B (MI 1.9) cells seemed out of proportion to their decreased receptor capacity for LPHA. The impaired mitogenic responses of leukemic cells from five patients were not enhanced when cocultured with normal lymphocytes. In contrast, cells from eight patients inhibited cocultured normal lymphocyte responses to LPHA by 94.3%. Sera from these patients and supernates from their cultured cells did not mediate this suppressor effect. These observations indicate that the decreased DNA synthesis observed in CLL is not an attribute of B cells and does not represent the expected response of a few residual normal T lymphocytes, but rather reflects impaired responses by all CLL cells. The defect does not relate to the density or function of membrane receptors for LPHA, to the presence of inhibitors in these patients' sera, or to depletion of helper T cells. Our data strongly suggest that one mechanism for the immunoincompetence observed in CLL reflects excessive suppressor-cell activity.
Left Ventricular Resynchronization Is Mandatory for Response to Cardiac Resynchronization Therapy
Authors: Gabe B. Bleeker, Sjoerd A. Mollema, Eduard R. Holman, Nico Van De Veire, Claudia Ypenburg, Eric Boersma, Ernst E. van der Wall, Martin J. Schalij, Jeroen J. Bax
Journal: Circulation (2007)

Background— Recent studies have demonstrated that a positive response to cardiac resynchronization therapy (CRT) is related to the presence of preimplantation left ventricular (LV) dyssynchrony. The time course and the extent of LV resynchronization after CRT implantation and their relationship to response are currently unknown. Methods and Results— One hundred consecutive patients scheduled for implantation of a CRT device were prospectively included if they met the following criteria: New York Heart Association class III to IV, LV ejection fraction ≤35%, QRS duration &gt;120 ms, and LV dyssynchrony (≥65 ms) on color-coded tissue Doppler imaging. Immediately after CRT implantation, LV dyssynchrony was reduced from 114±36 to 40±33 ms ( P &lt;0.001), which persisted at the 6-month follow-up (35±31 ms; P &lt;0.001 versus baseline; P =0.14 versus immediately after implantation). At the 6-month follow-up, 85% of patients were classified as responders to CRT (defined as &gt;10% reduction in LV end-systolic volume). Immediately after implantation, the responders to CRT demonstrated a significant reduction in LV dyssynchrony from 115±37 to 32±23 ms ( P &lt;0.001). The nonresponders, however, did not show a significant reduction in LV dyssynchrony (106±29 versus 79±44 ms; P =0.08). If the extent of acute LV resynchronization was &lt;20%, response to CRT at the 6-month follow-up was never observed. Conversely, 93% of patients with LV resynchronization ≥20% responded to CRT. Conclusions— LV resynchronization after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up in patients with echocardiographic evidence of LV dyssynchrony at baseline.
The TRAMP Complex Shows tRNA Editing Activity in S. cerevisiae
Authors: Helena Dickinson, Sandy Tretbar, Heike Betat, Mario Mörl
Journal: Molecular Biology and Evolution (2011)

Transfer RNA (tRNA) editing is a widespread processing phenomenon that alters the sequence of primary transcripts by base substitutions as well as nucleotide deletions and insertions at internal or terminal transcript positions. In the corresponding tRNAs, these events are an important prerequisite for the generation of functional transcripts. Although many editing events are well characterized at the reaction level, it is unclear in most cases from which ancestral activities the modern editing enzymes evolved. Here, we show that in Saccharomyces cerevisiae, the noncanonical poly(A) polymerase Trf4p in the TRAMP complex can be recruited for such an editing reaction at an introduced tRNA transcript. As a distributive polymerase involved in RNA surveillance and quality control, it has a broad substrate spectrum and binds only transiently to the transcripts, limiting the number of added nucleotides at the editing position. These features exactly meet the criteria for an ancestral enzyme of a modern editing activity. Accordingly, our observations are a strong experimental support for the hypothesis that enzymatic promiscuity serves as an evolutionary starting point for the emergence of new functions and activities.
Mycotic Infections
Authors: John Godwin Downing, Norman F. Conant
Journal: New England Journal of Medicine (1945)

NUMEROUS medical problems have been created by sudden changes in the living habits of large groups of the population. Emigration to different localities, the influx of workers into industries with which they have had no previous contact and the grouping of thousands of men in camps, both in this country and abroad, have contributed to the shifting problems of health. Diseases heretofore restricted to or endemic in certain areas or peculiar to certain industries have appeared sporadically and at times with epidemic proportions in areas or industries where they had not previously been reported. It is now necessary, therefore, that . . .
Phase II screening study of an LHRH analog, dexamethasone and somatostatin analog versus LHRH analogue with dexamethasone in HRPC
Authors: F. M. Calais da Silva, F. E. Calais da Silva, F. Gonçalves, T. Oliver
Journal: Journal of Clinical Oncology (2007)

15579 Background: As far as prostatic cancer is concerned, we know that somatuline (SMS) blocks GH, PRL, tissular growth factors (TGF) and that it has a direct antiproliferative cellular growth effect. The simultaneous administration of depot forms of SMS and LHRH analogues induced the greatest decrease in tumor growth. Methods: A randomised Phase II trial was carried out in M0 (PSA ≥ 20 ng/ml) and M1 patients with hormone refractory prostate cancer to simultaneously screen decapeptyl and dexamethasone, both with and without SMS (120 mg every 4 weeks), with respect to the PSA response rate, time to PSA progression, duration of survival and toxicity. Results: 72 patients with a median PSA of 77 ng/ml were randomised by 3 centers, 35 to decapeptyl, dexamethasone, both with and without SMS (DDS) and 37 to decapeptyl and dexamethasone (DD). 18 of 33 (54%) patients on DDS and 13 of 32 on DD (43%) had a PSA response (a decrease of at least 50% as compared to baseline). The median time to PSA was 5.5 months in the SMS group and 1.9 months in the group without SMS. At 6 months, 45.7% were PSA progression free in the SMS group versus 35.1% in the goup without SMS. The median time to PSA progression in PSA responders was 10.6 months in the SMS group and 13.9 months in the group without SMS. At 6 months, 73.7% of the PSA responders were progression free in the SMS group versus 81.3% in the group without SMS. 45 patients died (62.5%), 22 (62.9%) in the SMS group and 23 (62.2%) in the group without SMS. 15 and 19 of the deaths respectively were due to prostate cancer. The median duration of survival is 1.65 years in the SMS group and 1.48 years in the group without SMS. At 6 months, 85.7% were alive in the SMS group vs 78.1% in the group without SMS. At 12 months, 77.1% were alive in the SMS group vs 69.4% in the group without SMS. Conclusions: There is no evidence that SMS may have increased the incidence of side effects. The PSA response rate was slightly higher in the SMS group, 54% vs 43% and the median time to PSA progression in all patients appears to have been slightly longer in the SMS group. Fewer objective progressions were also observed in the SMS arm, 4 vs 12. These results suggest that SMS may add to the activity of decapeptyl and dexamethasone and thus have a role in the treatment of hormone refractory prostate cancer. No significant financial relationships to disclose.
Exploring the hidden heritability of inflammatory bowel disease
Authors: J. Satsangi, N. A. Kennedy, P. Henderson, D. C. Wilson, E. R. Nimmo
Journal: Gut (2011)

In recent years the inflammatory bowel diseases (IBD)—Crohn's disease and ulcerative colitis—have emerged as a model for all complex traits in the successful dissection of the molecular basis of inherited susceptibility by non-parametric linkage analysis1 2 and genome-wide association studies (GWAS).3–5 The recent meta-analyses of GWAS carried out by the International Inflammatory Bowel Disease Genetics Consortium have now reported the identification of 99 susceptibility loci involved in the pathogenesis of Crohn's disease and ulcerative colitis.4 5

These successes in candidate gene discovery have provided new insights into the pathogenetic mechanisms involved in the chronic intestinal inflammation associated with IBD. These data provide strong evidence that Crohn's disease and ulcerative colitis are related complex diseases, sharing some, but not all, susceptibility loci.5 It is clear that while some pathogenic pathways are implicated in both Crohn's disease and ulcerative colitis—notably, interleukin (IL)-23 signalling6 and Th17 cell activation,7 other innate immune mechanisms appear to be implicated in Crohn's disease only (eg, autophagy, and NOD2 signalling). Similarly, aspects of the maintenance of epithelial barrier function are most strongly implicated in ulcerative colitis.8 Furthermore, it is clear that many of the genetic determinants involved in IBD are also implicated in other complex disorders, such as type I diabetes and coeliac disease ( in press ).9 Both expected and unexpected associations are evident, and have provided avenues for further research.

Along with this exciting progress, however, new challenges have emerged for researchers in this complex field. Of the estimated heritability of IBD, which has been derived from concordance rates in twin pairs, <30% …
A missense mutation in the Kv1.1 voltage-gated potassium channel–encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia
Authors: Bob Glaudemans, Jenny van der Wijst, Rosana H. Scola, Paulo J. Lorenzoni, Angelien Heister, AnneMiete W. van der Kemp, Nine V. Knoers, Joost G. Hoenderop, René J. Bindels
Journal: Journal of Clinical Investigation (2009)

Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg2+ levels, with a prominent function for the Mg2+-transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane. Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K+) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K+ channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+ reabsorption.
Integrating Curricula on Human Trafficking Into Medical Education and Residency Training
Authors: Aimee M. Grace, Roy Ahn, Wendy Macias Konstantopoulos
Journal: JAMA Pediatrics (2014)

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