tbuckley/cabot-search huggingface dataset:
Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel Genes in the Garter Snake Thamnophis sirtalis
Authors: Joel W. McGlothlin, John P. Chuckalovcak, Daniel E. Janes, Scott V. Edwards, Chris R. Feldman, Edmund D. Brodie, Michael E. Pfrender, Edmund D. Brodie
Journal: Molecular Biology and Evolution (2014)

Members of a gene family expressed in a single species often experience common selection pressures. Consequently, the molecular basis of complex adaptations may be expected to involve parallel evolutionary changes in multiple paralogs. Here, we use bacterial artificial chromosome library scans to investigate the evolution of the voltage-gated sodium channel (Nav) family in the garter snake Thamnophis sirtalis, a predator of highly toxic Taricha newts. Newts possess tetrodotoxin (TTX), which blocks Nav's, arresting action potentials in nerves and muscle. Some Thamnophis populations have evolved resistance to extremely high levels of TTX. Previous work has identified amino acid sites in the skeletal muscle sodium channel Nav1.4 that confer resistance to TTX and vary across populations. We identify parallel evolution of TTX resistance in two additional Nav paralogs, Nav1.6 and 1.7, which are known to be expressed in the peripheral nervous system and should thus be exposed to ingested TTX. Each paralog contains at least one TTX-resistant substitution identical to a substitution previously identified in Nav1.4. These sites are fixed across populations, suggesting that the resistant peripheral nerves antedate resistant muscle. In contrast, three sodium channels expressed solely in the central nervous system (Nav1.1-1.3) showed no evidence of TTX resistance, consistent with protection from toxins by the blood-brain barrier. We also report the exon-intron structure of six Nav paralogs, the first such analysis for snake genes. Our results demonstrate that the molecular basis of adaptation may be both repeatable across members of a gene family and predictable based on functional considerations.
Angiotensin (A I, A II, A III) receptor characterization. Correlation of prostaglandin release with peptide degradation.
Authors: A L Blumberg, K Nishikawa, S E Denny, G R Marshall, P Needleman
Journal: Circulation Research (1977)

We examined the ability of the angiotensins (A I, A II, A III) to release a prostaglandin E (PGE)-like substance in the isolated Krebs' perfused kidney and mesenteric vasculature of the rabbit by parallel bioassay. In the kidney, the order of potency for PGE release was A II greater than A III greater than A I with ED50's of 36, 100, and 500 pmol, respectively. In the mesenteric preparation, on the other hand, the order of potency was A III greater than A II greater than A I with ED50's of 75, 125, and 500 pmol, respectively. During one transit through the kidney 72-76% of bioassayable A I and A II was degraded. A III was 89% metabolized. In contrast, the mesenteric vasculature inactivated only 27% of A II and 23% of A III. This data suggests an inverse relationship between renal peptide degradation and PGE release. For characterization of the renal angiotensin receptor-mediating PGE release, dissociation constants (KB) of the competitive angiotensin antagonists [IIe7]-A III and [Sar1, IIe3]-A II were determined with each angiotensin. KB values of the individual antaganists were not significantly different with A I, A II, or A III; this finding suggests that one renal angiotensin receptor is involved with PGE release.
Hepatitis C virus-induced vasculitis: therapeutic options
Authors: Patrice Cacoub, Benjamin Terrier, David Saadoun
Journal: Annals of the Rheumatic Diseases (2013)

Hepatitis C virus (HCV) is now well recognised as the main etiologic agent of mixed cryoglobulinaemia vasculitis (cryovas). New opportunities and problems in developing therapy have therefore emerged. Antiviral therapy with pegylated interferon-α and ribavirin (plus protease inhibitor in the case of HCV genotype 1 infection) should be considered as induction therapy for HCV-cryovas with mild to moderate disease severity and activity. An early virologic response to antiviral therapy is correlated with a complete clinical response of HCV-cryovas. In patients presenting with more severe disease (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease including ulcers and distal necrosis), an immunosuppression induction phase is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab plus an optimal antiviral agent is recommended, as it may target the downstream B cell arm of autoimmunity and the viral trigger. Careful monitoring for adverse effects is mandatory, since some manifestations of HCV-cryovas, such as peripheral neuropathy or skin ulcers, may worsen with interferon-based therapy. Clinicians should be aware of the possibility of malignant lymphoma when patients develop a relapse of cryovas without virological relapse. Room for other treatment strategies is very limited. Low-dose corticosteroids may help to control minor intermittent inflammatory signs such arthralgia but do not succeed in case of major organ involvement. Other immunosuppressants should be given only in case of refractory forms of HCV-cryovas, which are frequently associated with an underlying B cell lymphoma.
Alternative Management Strategies for Patients with Suspected Peptic Ulcer Disease
Authors: A. Mark Fendrick, Michael E. Chernew, Richard A. Hirth, Bernard S. Bloom
Journal: Annals of Internal Medicine (1995)

Objective: To estimate the clinical and economic effects of available invasive and noninvasive management strategies for peptic ulcer and Helicobacter pylori in persons with symptoms suggesting peptic ulcer disease. Design: Cost-effectiveness analysis using a decision analytic model. Intervention: 2 immediate endoscopy and 3 noninvasive diagnostic and treatment strategies were evaluated: 1) immediate endoscopy for peptic ulcer and biopsy for H. pylori; 2) immediate endoscopy without biopsy; 3) serologic test for H. pylori; 4) empiric treatment with antisecretory therapy; and 5) empiric treatment with antisecretory therapy and antibiotic agents to eradicate H. pylori. Measurements: Cost per ulcer cured and cost per patient treated. Results: The estimated costs per ulcer cured by strategy were as follows: 1) endoscopy and biopsy for H. pylori, $8045; 2) endoscopy without biopsy, $6984; 3) serologic test for H. pylori, $4541; 4) empiric antisecretory therapy, $4835; and 5) empiric antisecretory and antibiotic therapy, $4155. The predicted costs per patient treated were as follows: 1) endoscopy and biopsy for H. pylori, $1584; 2) endoscopy without biopsy, $1375; 3) serologic test for H. pylori, $894; 4) empiric antisecretory therapy, $952; and 5) empiric antisecretory and antibiotic therapy, $818. The cost-effectiveness advantage of the noninvasive strategies diminished as the cost of endoscopy decreased or as the probability of recurrent symptoms increased in patients initially managed without endoscopy. Conclusion: Endoscopy, although costly, precisely guided diagnosis and treatment and thus potentially reduced the number of patients inappropriately treated. However, the safety and effectiveness of less expensive, less invasive diagnostic and treatment strategies strongly support initial noninvasive care of symptomatic persons thought to have peptic ulcer disease.
In Vivo Platelet–Endothelial Cell Interactions in Response to Major Histocompatibility Complex Alloantibody
Authors: Craig N. Morrell, Kazunori Murata, Anne Marie Swaim, Emily Mason, Tanika V. Martin, Laura E. Thompson, Mathew Ballard, Karen Fox-Talbot, Barbara Wasowska, William M. Baldwin
Journal: Circulation Research (2008)

Platelets recruit leukocytes and mediate interactions between leukocytes and endothelial cells. Most studies examining this important platelet immune function have focused on the development of atherosclerosis, but similar mechanisms may contribute to acute and chronic vascular lesions in transplants. Platelets have been described as markers of transplant rejection, but little investigation has critically examined a role for platelets in transplant vasculopathy and, in particular, alloantibody-mediated transplant rejection. We now demonstrate using a skin transplant model that alloantibody indirectly induces platelet activation and rolling in vivo. Repeated IgG2a alloantibody injections result in sustained platelet-endothelial interactions and vascular pathology, including von Willebrand factor release, small platelet thrombi, and complement deposition. Maintenance of continued platelet-endothelial interactions are dependent on complement activation. Furthermore, we demonstrate that platelets recruit leukocytes to sites of alloantibody deposition and sustain leukocyte-endothelial cell interactions in vivo. Taken together, our model demonstrates an important role for platelets in alloantibody induced transplant rejection.
Breast Tissue Composition and Susceptibility to Breast Cancer
Authors: N. F. Boyd, L. J. Martin, M. Bronskill, M. J. Yaffe, N. Duric, S. Minkin
Journal: JNCI Journal of the National Cancer Institute (2010)

Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.
Normality and abnormality in psychiatry.
Authors: J G Edwards
Journal: BMJ (1978)

In addition, a recent study4 of testicular morphology in boys treated for acute lymphoblastic leukaemia (ALL) with combination chemotherapy found no evidence of a relation- ship between the degree of tubular damage and the age at which the subject first received cytotoxic therapy.Therefore the prepubertal testis would appear to be just as vulnerable to cytotoxic damage as the pubertal testis.Finally, it is true that we observed5 depressed ovarian function in a proportion of girls previously treated for ALL with combination chemotherapy.However, the evidence indi- cated direct damage to the ovaries due to the chemotherapy rather than as a consequence of radiation-induced hypothalamic-pituitary damage.
Percutaneous Heart Valve Replacement for Aortic Stenosis: State of the Evidence
Authors: Remy R. Coeytaux
Journal: Annals of Internal Medicine (2010)

Surgical aortic valve replacement (SAVR) is the only treatment known to improve symptoms and survival in patients with severe, symptomatic aortic stenosis. Perioperative mortality, however, is high among many patients for whom SAVR may be indicated. Percutaneous heart valve replacement (PHVR) is an emerging, catheter-based technology that allows for implantation of a prosthetic valve without open heart surgery. This review describes the available literature on PHVR for aortic stenosis, which comprised 84 published reports representing 76 distinct studies and 2375 unique patients. Successful implantation was achieved in 94% of patients; 30-day survival was 89%. Differences between patients undergoing PHVR and those typically selected for SAVR make full interpretation of these results difficult. A large, multicenter, randomized, controlled trial comparing PHVR with SAVR or medical management was recently completed, with initial results expected in September 2010. Pending publication of findings from that trial, the available evidence is inadequate to determine the most appropriate clinical role of PHVR or the specific patient populations for whom it might eventually be indicated.
Field and laboratory testing in young elite soccer players
Authors: K Chamari, Y Hachana, Y B Ahmed, O Galy, F Sghaïer, J-C Chatard, O Hue, U Wisløff
Journal: British Journal of Sports Medicine (2004)

Aim: To determine if there are correlations between the physical fitness of young soccer players assessed by field and laboratory testing. Methods: Thirty four male soccer players took part in the study (mean (SD) age 17.5 (1.1) years, height 177.8 (6.7) cm, weight 70.5 (6.4) kg). Maximal oxygen uptake (V o 2 max ) during treadmill running and vertical jump height on a force platform were measured in the laboratory. Field tests consisted of a soccer specific endurance test (Bangsbo test) and 30 m sprint with 10 m lap times. Results: The Bangsbo test correlated with the lowest velocity associated with V o 2 max ( v V o 2 max ; R 2 = 0.55, p&lt;0.001), but not with V o 2 max . Sprint times at 30 m and 20 m were related to peak extension velocity and peak extension force measured during vertical jumping, but not to vertical jump height per se. The jumping force and velocity could explain 46% of the 30 m sprint performance ( R 2 = 0.46, p&lt;0.001). Conclusion: The Bangsbo test and 30 m sprint test correlate with v V o 2 max and vertical jump force and velocity respectively. The Bangsbo test does not give a good estimate of V o 2 max in young soccer players.
Low-Friction Arthroplasty
Authors: F. Bruce Kimball
Journal: JAMA (1972)

<h3>To the Editor.—</h3> Eftekhar's article, "Low-Friction Arthroplasty: Indications, Contraindications, and Complications" (<b>218</b>:705, 1971), was timely because it coincided with the FDA release of the acrylic cement used in the operation. The paper is open to criticism because it offers incomplete statistical data to support its many conclusions. Eftekhar has had extensive experience in over 900 cases, yet he denies the reader the opportunity to judge the validity of his conclusions by an examination of data from this large series. All orthopedists are aware of the infection problem in patients who undergo total hip replacement, yet no data are offered from Eftekhar's series. With regard to postoperative dislocations, the author again does not indicate the incidence, or the factors that may have influenced his results. He condemns failure to remove the trochanter but there is no evidence to support this condemnation. In San Diego over 250 total hip replacements have
BMN 673, a Novel and Highly Potent PARP1/2 Inhibitor for the Treatment of Human Cancers with DNA Repair Deficiency
Authors: Yuqiao Shen, Farah L. Rehman, Ying Feng, Julia Boshuizen, Ilirjana Bajrami, Richard Elliott, Bing Wang, Christopher J. Lord, Leonard E. Post, Alan Ashworth
Journal: Clinical Cancer Research (2013)

Abstract Purpose: PARP1/2 inhibitors are a class of anticancer agents that target tumor-specific defects in DNA repair. Here, we describe BMN 673, a novel, highly potent PARP1/2 inhibitor with favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. Experimental Design: Potency and selectivity of BMN 673 was determined by biochemical assays. Anticancer activity either as a single-agent or in combination with other antitumor agents was evaluated both in vitro and in xenograft cancer models. Results: BMN 673 is a potent PARP1/2 inhibitor (PARP1 IC50 = 0.57 nmol/L), but it does not inhibit other enzymes that we have tested. BMN 673 exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as olaparib, rucaparib, and veliparib). In vitro, BMN 673 selectively targeted tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. BMN 673 is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of BMN 673 elicited remarkable antitumor activity in vivo; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency were profoundly sensitive to oral BMN 673 treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects were also found when BMN 673 was combined with temozolomide, SN38, or platinum drugs. Conclusion: BMN 673 is currently in early-phase clinical development and represents a promising PARP1/2 inhibitor with potentially advantageous features in its drug class. Clin Cancer Res; 19(18); 5003–15. ©2013 AACR.
Diagnosis of valvular heart disease using transcutaneous Doppler ultrasound
Authors: A. O. BRUBAKK, B. A. J. ANGELSEN, L. HATLE
Journal: Cardiovascular Research (1977)

An ultrasonic Doppler instrument capable of measuring mean and maximum velocities inside a small sample volume is presented. The instrument has been used for determining velocities in normal and diseased heart valves. A method is described for identifying the different heart valves, based on their relation to one another as well as the form of the velocity curve. The pressure drop across the mitral valve can be determined from the maximum velocity and the mean velocity can be used to determine the degree of aortic insufficiency. Recordings of mean and maximum velocities can give an indication of the form of the whole spectrum, thus making complete frequency analysis unnecessary for most purposes.
The Ccr7 Ligand ELC (Ccl19) Is Transcytosed in High Endothelial Venules and Mediates T Cell Recruitment
Authors: Espen S. Baekkevold, Takeshi Yamanaka, Roger T. Palframan, Hege S. Carlsen, Finn P. Reinholt, Ulrich H. von Andrian, Per Brandtzaeg, Guttorm Haraldsen
Journal: The Journal of Experimental Medicine (2001)

Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEV-derived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (Epstein-Barr virus–induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC (plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest.
Natural IgE Production in the Absence of MHC Class II Cognate Help
Authors: Kathy D. McCoy, Nicola L. Harris, Philipp Diener, Sarah Hatak, Bernhard Odermatt, Lars Hangartner, Beatrice M. Senn, Benjamin J. Marsland, Markus B. Geuking, Hans Hengartner, Andrew J.S. Macpherson, Rolf M. Zinkernagel
Journal: Immunity (2006)
Targeted Anticytokine Therapy in Patients With Chronic Heart Failure
Authors: Douglas L. Mann, John J.V. McMurray, Milton Packer, Karl Swedberg, Jeffrey S. Borer, Wilson S. Colucci, Jacques Djian, Helmut Drexler, Arthur Feldman, Lars Kober, Henry Krum, Peter Liu, Markku Nieminen, Luigi Tavazzi, Dirk Jan van Veldhuisen, Anders Waldenstrom, Marshelle Warren, Arne Westheim, Faiez Zannad, Thomas Fleming
Journal: Circulation (2004)

Background— Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Methods and Results— Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction ≤0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE ( P =0.17) or RECOVER ( P =0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P =0.33). Conclusions— The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
Abrogation by subsequent feeding of antibody response including IgE, in parenterally immunized mice.
Authors: S Lafont, C André, F André, J Gillon, M C Fargier
Journal: The Journal of Experimental Medicine (1982)

We have investigated the possibility of oral administration of ovalbumin (OVA) to prevent a secondary antibody response and interrupt reaginic antibody production. Repeated feeding seems necessary for both. Quality of results was dependent on the number of ingestions. Differences in abrogation of antibody response between mice strains were observed. Best results were obtained with AKR mice, good suppression was seen in C3H strain, and inconsistent results were obtained with DBA/2. 10 OVA oral doses were necessary to prevent a secondary antibody response in parenterally immunized mice, but 4 doses interrupted reaginic production in sensitized AKR mice. These results demonstrate that antigen feeding can prevent a secondary antibody response and interrupt reaginic antibody production.