tbuckley/cabot-search huggingface dataset:
Differences in transient outward currents of feline endocardial and epicardial myocytes.
Authors: T Furukawa, R J Myerburg, N Furukawa, A L Bassett, S Kimura
Journal: Circulation Research (1990)

Whole-cell voltage-clamp experiments were performed on enzymatically dissociated single ventricular myocytes harvested from feline endocardial and epicardial surfaces. The studies were designed to test the hypothesis that the differences in the amplitude of transient outward current (Ito) contribute to the difference in action potential configuration between endocardial and epicardial myocytes. In the control state, action potentials recorded from epicardial cells demonstrated a prominent notch between phases 1 and 2, and membrane current recordings displayed a prominent Ito, whereas in endocardial cells the notch in action potentials and Ito were small. External application of 4-aminopyridine (2 mM) reduced the amplitudes of notch and Ito in epicardial cells but not in endocardial cells. After application of 4-aminopyridine (2 mM) and caffeine (5 mM), the notch and Ito were abolished completely in both endocardial and epicardial cells. The first component of Ito (Ito1) was present in all epicardial cells studied (n = 20); it was absent in 12 of the 20 endocardial cells, and a small Ito1 was present in the remaining eight endocardial cells. The mean amplitude of Ito1 was significantly greater in epicardial than in endocardial cells. At a test voltage of +80 mV, the amplitude of Ito1 was 102.0 +/- 47.7 pA/pF in epicardial cells and 3.3 +/- 3.3 pA/pF in endocardial cells (p less than 0.01). The second component of Ito (Ito2) was present in all endocardial (n = 30) and epicardial (n = 30) cells studied. The amplitude of Ito2 was significantly greater in epicardial than in endocardial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Determinants of sensitization of carotid baroreceptors by pulsatile pressure in dogs.
Authors: M W Chapleau, F M Abboud
Journal: Circulation Research (1989)

The threshold pressure of single baroreceptor units is decreased after compared with before exposure to pulsatile pressure according to previous studies in our laboratory. The purpose of the present study is to characterize the determinants of sensitization of arterial baroreceptors by pulsatile pressure. Carotid sinus nerve activity was recorded in dogs anesthetized with chloralose. Two indexes of baroreceptor "sensitivity" were obtained by comparing nerve activity before and immediately after exposure of the isolated carotid sinus to pulsatile pressure for periods up to 10 minutes. Sensitization occurred 1) when the threshold pressure of single baroreceptor units determined with a slow nonpulsatile ramp decreased after as compared with before pulsing and 2) when multiple unit activity increased after as compared with before pulsing at various mean levels of static pressure. Sensitization was evident after pulsing at mean pressure of 50 and 100 mm Hg, but not at 150 and 200 mm Hg, and was caused by the pulsatile change in diameter or deformation and not by the pulsatile change in wall tension. The magnitude of the effect was directly related to the duration of the pulsing period and to the frequency and amplitude of the pressure pulses. The sensitization could not be explained by increased diameter (sonomicrometers) or strain of the carotid sinus at the same pressure after pulsing; thus, there was an increase in "strain sensitivity" that outlasted the period of pulsing by up to several minutes. In most experiments the shift from static to pulsatile pressure at 50 and 100 mm Hg caused an increase in nerve activity, yet sensitization occurred after pulsing when one would have expected postexcitatory hyperpolarization or depression of activity upon return to static pressure. The sensitization was not caused by the release of prostacyclin from the endothelium since it was not reduced after endothelial denudation or inhibition of cyclooxygenase with indomethacin (30-80 microM) or ibuprofen (250 microM). We speculate that sensitization of baroreceptors by pulsatile pressure may contribute to the decreased sympathetic activity after periods of elevated pulse pressure (e.g., after exercise). We also propose that the decreased sensitivity of baroreceptors after acute elevation of arterial pressure (acute resetting) may be offset in part by the sensitizing effect of increased pulsatile stretch.
Feeder vessel photocoagulation for subfoveal CNV11The following letters address an article that appeared in the April 1998 issue of the Journal:Feeder Vessel Photocoagulation of Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration (Ophthalmology 1998;105:662–9)
Authors: Steven M Bloom
Journal: Ophthalmology (1998)
Hypoxia-Inducible Factor 1α Expression as an Intrinsic Marker of Hypoxia
Authors: Gillian J. Hutchison, Helen R. Valentine, Juliette A. Loncaster, Susan E. Davidson, Robert D. Hunter, Stephen A. Roberts, Adrian L. Harris, Ian J. Stratford, Patricia M. Price, Catharine M. L. West
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Hypoxia-inducible factor (HIF)-1α expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. Experimental Design: HIF-1α expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. Results: High HIF-1α expression showed a weak correlation with low pO2 (r = −0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1α and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1α expression and radiotherapy outcome was examined in 99 patients. HIF-1α expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1α alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1α expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1α and tumor size for survival (P = 0.046) and local control (P = 0.009). Conclusions: In this study, HIF-1α had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1α expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1α. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.
Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies
Authors: Stefania Nobili, Enrico Mini, Ida Landini, Chiara Gabbiani, Angela Casini, Luigi Messori
Journal: Medicinal Research Reviews (2009)

Gold compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of gold(I) and gold(III) compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the gold center confer very interesting and innovative pharmacological profiles to gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer gold compounds, carried out either in vitro or in vivo. The available investigations of anticancer gold compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic gold compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of gold compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 3, 550–580, 2010
Eccentric strengthening effect of hip-adductor training with elastic bands in soccer players: a randomised controlled trial
Authors: Jesper Jensen, Per Hölmich, Thomas Bandholm, Mette K Zebis, Lars L Andersen, Kristian Thorborg
Journal: British Journal of Sports Medicine (2012)

Background Soccer players with weak hip-adductor muscles are at increased risk of sustaining groin injuries. Therefore, a simple hip-adductor strengthening programme for prevention of groin injuries is needed. Objective We aimed to investigate the effect of an 8-week hip-adductor strengthening programme, including one hip-adduction exercise, on eccentric and isometric hip-adduction strength, using elastic bands as external load. Methods Thirty-four healthy, sub-elite soccer players, mean (±SD) age of 22.1 (±3.3) years, were randomised to either training or control. During the mid-season break, the training group performed 8 weeks of supervised, progressive hip-adduction strength training using elastic bands. The participants performed two training sessions per week (weeks 1–2) with 3×15 repetition maximum loading (RM), three training sessions per week (weeks 3–6) with 3×10 RM and three training sessions per week (weeks 7–8) with 3×8 RM. Eccentric hip-adduction (EHAD), isometric hip-adduction (IHAD) and isometric hip-abduction (IHAB) strength, and the IHAD/IHAB ratio were measured assessor-blinded preintervention and postintervention, using reliable hand-held dynamometry procedures. Results In the training group, EHAD strength increased by 30% (p&lt;0.001). In the control group, EHAD strength increased by 17% (p&lt;0.001), but the increase was significantly larger in the training group compared with the control group (p=0.044). No other significant between-group strength-differences in IHAD, IHAB or the IHAD/IHAB ratio existed (p&gt;0.05). Conclusions 8 weeks of hip-adduction strength training, using elastic bands, induce a relevant increase in eccentric hip-adduction strength in soccer players, and thus may have implications as a promising approach towards prevention of groin injuries in soccer.
Genetic Analysis of Mesangial Matrix Expansion in Aging Mice and Identification of Far2 as a Candidate Gene
Authors: Gerda A. Noordmans, Christina R. Caputo, Yuan Huang, Susan M. Sheehan, Marian Bulthuis, Peter Heeringa, Jan-Luuk Hillebrands, Harry van Goor, Ron Korstanje
Journal: Journal of the American Society of Nephrology (2013)

Aging of the kidney is associated with renal damage, in particular mesangial matrix expansion (MME). Identifying the genes involved in this process will help to unravel the mechanisms of aging and aid in the design of novel therapeutic modalities aimed at prevention and regression. In this study, structural changes in glomeruli of 24 inbred mouse strains were characterized in male mice at 6, 12, and 20 months of age. Haplotype association mapping was used to determine genetic loci associated with the presence of MME at 20 months. This analysis identified a significant association with a 200-kb haplotype block on chromosome 6 containing Far2. Sequencing revealed that mouse strains with MME contain a 9-bp sequence in the 5' untranslated region of Far2 that is absent in most of the strains without MME. Real-time PCR showed a two-fold increase in the expression of Far2 in the kidneys of strains with the insert, and subsequent experiments performed in vitro with luciferase reporter vectors showed that this sequence difference causes differential expression of Far2. Overexpression of Far2 in a mouse mesangial cell line induced upregulation of platelet activating factor and the fibrotic marker TGF-β. This upregulation of MME-promoting factors may result, in part, from the FAR2-catalyzed reduction of fatty acyl-coenzyme A to fatty alcohols, which are possible precursors of platelet activating factor. Overall, these data suggest the identification of a novel pathway involved in renal aging that may yield therapeutic targets for reducing MME.
Park's story and Winters' tale: alternate allocation clinical trials in turn of the century America
Authors: Scott H Podolsky, George Davey Smith
Journal: Journal of the Royal Society of Medicine (2011)

In 1898, Johannes Fibiger of Copenhagen, in the setting of scepticism about the efficacy of diphtheria antitoxin, famously allocated 484 patients admitted to his hospital on alternate days to either receive or not receive antitoxin in order to test its utility.1–3 Over the subsequent half-century before the Medical Research Council's randomized control study of streptomycin for pulmonary tuberculosis, alternate allocation would emerge as an increasingly utilized and respected methodological tool for determining therapeutic efficacy.4–6 Yet the advent and early dissemination of this methodology – and the resistance to its wider application – is only now beginning to be seriously researched.

William H Park (1863–1939), the longstanding director of the laboratories of the New York Board of Health, has been justifiably honoured for having saved countless lives through the use of diphtheria antitoxin and immunization in New York City at the end of the 19th century and beginning of the 20th century.7 During those same years, Park was closely associated with some of the most sophisticated and visible therapeutic trials in America (and the world). In addition to using alternate allocation of patients to treatment comparison groups, they used double-blinding,8 multisite collaboration, and statistically compared treatment groups, including the use of statistical synthesis (meta-analysis).9 

Park would claim, like Fibiger, to have first conducted such an alternate allocation study in the 1890s in the setting of scepticism regarding the utility of diphtheria antitoxin. Yet a deeper investigation of the context of Park's apparent study reveals not only a surprise twist, but important insights into the advent of, and resistance to, the alternate allocation method in the United States, and possibly further afield.
Migratory Properties of Naive, Effector, and Memory Cd8+ T Cells
Authors: Wolfgang Weninger, Maura A. Crowley, N. Manjunath, Ulrich H. von Andrian
Journal: The Journal of Experimental Medicine (2001)

It has been proposed that two different antigen-experienced T cell subsets may be distinguishable by their preferential ability to home to lymphoid organs (central memory cells) or nonlymphoid tissues (effector memory/effector cells). We have shown recently that murine antigen-primed CD8+ T cells cultured in interleukin (IL)-15 (CD8IL-15) resemble central memory cells in phenotype and function. In contrast, primed CD8+ T cells cultured in IL-2 (CD8IL-2) become cytotoxic effector cells. Here, the migratory behavior of these two subsets was investigated. Naive, CD8IL-15 cells and, to a lesser degree, CD8IL-2 cells localized to T cell areas in the spleen, but only naive and CD8IL-15 cells homed to lymph nodes (LNs) and Peyer's patches. Intravital microscopy of peripheral LNs revealed that CD8IL-15 cells, but not CD8IL-2 cells, rolled and arrested in high endothelial venules (HEVs). Migration of CD8IL-15 cells to LNs depended on L-selectin and required chemokines that bind CC chemokine receptor (CCR)7. Both antigen-experienced populations, but not naive T cells, responded to inflammatory chemokines and accumulated at sites of inflammation. However, CD8IL-2 cells were 12 times more efficient in migrating to inflamed peritoneum than CD8IL-15 cells. Furthermore, CD8IL-15 cells proliferated rapidly upon reencounter with antigen at sites of inflammation. Thus, central memory-like CD8IL-15 cells home avidly to lymphoid organs and moderately to sites of inflammation, where they mediate rapid recall responses, whereas CD8IL-2 effector T cells accumulate in inflamed tissues, but are excluded from most lymphoid organs.
Failure of long surviving, passively enhanced kidney allografts to provoke T-dependent alloimmunity. I. Retransplantation of (AS X AUG)F1 kidneys into secondary AS recipients.
Authors: J R Batchelor, K I Welsh, A Maynard, H Burgos
Journal: The Journal of Experimental Medicine (1979)

Long survival of (AS X AUG)F1 rat kidney allografts in AS recipients was induced by passive enhancement with AS anti-AUG antiserum at the time of grafting. After 1-3 mo, the kidney allografts were transferred to second AS recipients, either naive or sensitized against AUG tissue. Naive second recipients did not reject the grafts acutely and failed to mount T-dependent immunity against AUG targets. When later challenged with spleen cells carrying the AUG haplotype, the naive second AS recipients showed strong IgM, IgG, and cytotoxic T-cell responses after grafting, and the kidneys were rapidly destroyed by immune rejection in all but one rat. It is concluded that long-surviving kidney allografts fail to activate helper T cells and induce in naive second recipients the same state of unresponsiveness observed in the first recipient.
Cancer Arising After Pancreas and/or Kidney Transplantation in a Series of 99 Diabetic Patients
Authors: Sabina Martinenghi, Giacomo Dell'Antonio, Antonio Secchi, Valerio Di Carlo, Guido Pozza
Journal: Diabetes Care (1997)

OBJECTIVE Recipients of solid organ transplants have an increased risk of developing certain types of malignancies as compared with the general population. The majority of the literature has reported on neoplasms in kidney and heart transplant recipients. RESEARCH DESIGN AND METHODS We describe 9 neoplasms occurring in 7 out of 73 IDDM patients after simultaneous pancreas and kidney transplantation. No cases were recorded among 26 IDDM recipients of kidney transplantation. RESULTS Among the neoplasms found were 2 cases of posttransplant lymphoproliferative disorder (PTLD), malignant melanoma, basal-cell and squamous-cell carcinoma of the skin in the same patient, squamous-cell carcinoma in situ of the vulva, hepatocarcinoma, small-cell lung cancer, and ductal carcinoma of the breast. Four patients died. Among immunological risk factors, over-immunosuppression for steroid-resistant kidney rejection was administered only in the 2 cases of PTLD. CONCLUSIONS Increased dosage of immunosuppressive agents may be necessary in some patients of prevent or treat rejection in view of their reduced survival on hemodialysis.
Impaired ability of patients with familial isolated vitamin E deficiency to incorporate alpha-tocopherol into lipoproteins secreted by the liver.
Authors: M G Traber, R J Sokol, G W Burton, K U Ingold, A M Papas, J E Huffaker, H J Kayden
Journal: Journal of Clinical Investigation (1990)

Plasma and lipoprotein alpha-tocopherol concentrations of four patients with familial isolated vitamin E deficiency and six control subjects were observed for 4 d after an oral dose (approximately 15 mg) of RRR-alpha-tocopheryl acetate labeled with six deuterium atoms (d6-tocopherol). Chylomicron d6-tocopherol concentrations were similar in the two groups. d6-Tocopherol concentrations of plasma, very low (VLDL), low (LDL), and high (HDL) density lipoproteins were similar in the two groups only during the first 12 h; then these were significantly lower, and the rate of disappearance faster, in the patients. The times (tmax) of the maximum chylomicron d6-tocopherol concentrations were similar for the two groups, but tmax values in the controls increased in the order: chylomicrons less than VLDL less than or equal to LDL approximately HDL, while the corresponding values in the patients were similar to the chylomicron tmax. Thus, plasma d6-tocopherol in controls increased during chylomicron and VLDL catabolism, whereas in patients it increased only during chylomicron catabolism, thereby resulting in a premature and faster decline in the plasma tocopherol concentration due to a lack of d6-tocopherol secretion from the liver. We suggest that these patients are lacking or have a defective liver "tocopherol binding protein" that incorporates alpha-tocopherol into nascent VLDL.
Mortality in asthmatics over 15 yrs: a dynamic cohort study from 1983–1998
Authors: C.K. Connolly, S.M. Alcock, R.J. Prescott
Journal: European Respiratory Journal (2002)

The Darlington and Northallerton long-term asthma study observes outcome in asthmatics in the light of potential explanatory variables recorded prospectively. This paper reports changes in mortality during the study, and assesses the relevant risk factors. All asthmatics attending secondary care were recruited at 5‐yr intervals from 1983 and reviewed 5 yrs later. Demographic and functional variables, including a formal estimate of best function were recorded prospectively. The dynamic cohort comprised 1,148 asthmatics with 95% follow-up, enabling 612 observations in the period 1983/1988, 774 in 1988/93 and 823 in 1993/98, with 101, 111 and 100 deaths respectively. Principal risk factors for mortality were lower social class and best forced vital capacity. Mortality relative to 1983 halved by 1993/98 and was reduced against the Darlington population, despite an entry forced expiratory volume in one second of 84.7%. There was no change in predictive value of risk factors during the study period, or with date of entry. This study demonstrates a consistent reduction in mortality, which was not entirely a survivor effect, but may be associated with changes in management. By 1993/98 mortality approximated to that of the local reference population despite a lower than predicted forced expiratory volume in one second.
Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo
Authors: Erinn B. Rankin, Mangatt P. Biju, Qingdu Liu, Travis L. Unger, Jennifer Rha, Randall S. Johnson, M. Celeste Simon, Brian Keith, Volker H. Haase
Journal: Journal of Clinical Investigation (2007)

Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1α and/or Hif-2α (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel–Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1α. Here we show that conditional inactivation of Hif-2α in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2α but not Hif-1α and that the hypoxic induction of liver Epo in anemic adults was Hif-2α dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1α dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver.