tbuckley/cabot-search huggingface dataset:
Binding of longer Aβ to transmembrane domain 1 of presenilin 1 impacts on Aβ42 generation
Authors: Yu Ohki, Naoaki Shimada, Aya Tominaga, Satoko Osawa, Takuya Higo, Satoshi Yokoshima, Tohru Fukuyama, Taisuke Tomita, Takeshi Iwatsubo
Journal: Molecular Neurodegeneration (2014)

Amyloid-β peptide ending at 42nd residue (Aβ42) is believed as a pathogenic peptide for Alzheimer disease. Although γ-secretase is a responsible protease to generate Aβ through a processive cleavage, the proteolytic mechanism of γ-secretase at molecular level is poorly understood. We found that the transmembrane domain (TMD) 1 of presenilin (PS) 1, a catalytic subunit for the γ-secretase, as a key modulatory domain for Aβ42 production. Aβ42-lowering and -raising γ-secretase modulators (GSMs) directly targeted TMD1 of PS1 and affected its structure. A point mutation in TMD1 caused an aberrant secretion of longer Aβ species including Aβ45 that are the precursor of Aβ42. We further found that the helical surface of TMD1 is involved in the binding of Aβ45/48 and that the binding was altered by GSMs as well as TMD1 mutation. Binding between PS1 TMD1 and longer Aβ is critical for Aβ42 production.
Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia
Authors: Richard M. Bergenstal, David C. Klonoff, Satish K. Garg, Bruce W. Bode, Melissa Meredith, Robert H. Slover, Andrew J. Ahmann, John B. Welsh, Scott W. Lee, Francine R. Kaufman
Journal: New England Journal of Medicine (2013)

The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor-augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia.We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold-suspend events were analyzed with respect to subsequent sensor glucose values.A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980 ± 1200 mg per deciliter [54.4 ± 66.6 mmol per liter] × minutes vs. 1568 ± 1995 mg per deciliter [87.0 ± 110.7 mmol per liter] × minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5 ± 1.0 vs. 2.2 ± 1.3 per patient-week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6 ± 40.7 mg per deciliter (5.1 ± 2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis.This study showed that over a 3-month period the use of sensor-augmented insulin-pump therapy with the threshold-suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values. (Funded by Medtronic MiniMed; ASPIRE ClinicalTrials.gov number, NCT01497938.).
Changes in coronary and collateral flows and adequacy of perfusion in the dog following one and three months of circumflex occlusion.
Authors: K W Scheel, T A Galindez, B Cook, R J Rodriguez, L A Ingram
Journal: Circulation Research (1976)

We investigated changes in circumflex, left anterior descending (LAD), and right coronary artery flows as well as changes in collateral flows to these vessels after long-term circumflex occlusion. Coronary and collateral flows of each vessel were determined simultaneously in an isolated heart preparation in which the vasculature was maximally dilated with dipyridamole. The resistances as related to total heart weight of the circumflex, LAD, and right coronary arteries of 16 control dogs were found to be 0.59 +/- 0.06, 0.93 +/- 0.09, and 2.37 +/- 0.17 (mean +/- SEM) mm Hg/[(ml/min)/100 g], respectively. Total minimal coronary resistance was 0.21 +/- 0.01. In 10 dogs subjected to occlusion for 1 month no significant change in circumflex coronary resistance was observed, but the resistance of the unimpaired vessels decreased significantly. The resistances of the LAD and right coronary arteries were 0.66 +/-0.04 and 1.72 +/- 0.13, respectively. Both values were considerably less (P less than 0.01) than control. In nine dogs subjected to occlusion for 3 months the resistance of the unimpaired LAD and right arteries, as well as the circumflex coronary resitance, were not significantly different from control. We also found that retrograde flows for all vessels increased 7-fold after 1 month and 10.5-fold (relative to control) after 3 months of occlusion. From these data we conclude that vascular adaptations, which occurred in response to an ischemic stimulus, are responsible for the long-term regulation of the metabolic needs of the myocardium.
Low Efficiency of Ca <sup>2+</sup> Entry Through the Na <sup>+</sup> -Ca <sup>2+</sup> Exchanger as Trigger for Ca <sup>2+</sup> Release From the Sarcoplasmic Reticulum
Authors: Karin R. Sipido, Micheline Maes, Frans Van de Werf
Journal: Circulation Research (1997)

Abstract It has been proposed that Ca 2+ entry through the Na + -Ca 2+ exchanger can contribute significantly to the trigger for Ca 2+ release from the sarcoplasmic reticulum (SR). We have compared the characteristics of Ca 2+ release triggered by reverse-mode Na + -Ca 2+ exchange and by L-type Ca 2+ current ( I CaL ) during depolarizing steps in single guinea pig ventricular myocytes (whole-cell voltage clamp, fluo 3 and fura-red as [Ca 2+ ] i indicators, 36±1°C, K + -based pipette solution with 20 mmol/L [Na + ]). Conditioning pulses to +60 mV ensured comparable Ca 2+ loading of the SR. In the presence of I CaL , [Ca 2+ ] i transients typically have an early and rapid rising phase reflecting Ca 2+ release, which has a bell-shaped voltage dependence with a peak at +10 mV. With Ca 2+ entry through Na + -Ca 2+ exchange only (20 μmol/L nisoldipine), Ca 2+ release flux from the SR is decreased and directly related to the amplitude of the depolarizing step. Ca 2+ release is preceded by a significant delay (81±21 ms at +20 mV, 24±4 ms at +70 mV) related to Ca 2+ entry through the exchanger. Triggered release interrupts Ca 2+ entry, as evidenced by reversal of the exchanger current. At potentials positive to +40 mV, Ca 2+ influx through Na + -Ca 2+ exchange, calculated from the outward exchange current, reaches magnitudes comparable to I CaL , but Ca 2+ release due to reverse-mode Na + -Ca 2+ exchange still has a significant delay. We calculated trigger efficiency as the ratio between the maximal rate of Ca 2+ release and the Ca 2+ influx preceding this release; efficiency of reverse-mode Na + -Ca 2+ exchange is approximately four times less than that of I CaL . With both I CaL and reverse-mode Na + -Ca 2+ exchange present, Ca 2+ release is triggered by I CaL , and a contribution of reverse-mode Na + -Ca 2+ exchange to the trigger could not be detected at potentials below +60 mV. These characteristics of reverse-mode Na + -Ca 2+ exchange predict that its role as a trigger for Ca 2+ release during the action potential is likely to be negligible.
Recurrent annular erythema in juvenile chronic myelogenous leukaemia
Authors: None Anzai, None Kikuchi, None Kinoshita, None Nishikawa
Journal: British Journal of Dermatology (1998)

Juvenile chronic myelogenous leukaemia (JCML) is a rare haematological malignancy of myelomonocytic lineage that affects patients less than 4 years of age and is known as an entity different from adult-type chronic myelogenous leukaemia. In JCML, skin manifestations are relatively common but most of them have been reported as a non-specific eruption, which histologically may show changes resembling neurofibromatosis or xanthogranuloma. We present a 2-year-old boy with JCML who developed a recurrent annular erythema in which leukaemic infiltrates were confirmed histologically, even though his bone marrow examination suggested that he remained in haematological remission.
Chronic Kidney Disease, Mortality, and Treatment Strategies among Patients with Clinically Significant Coronary Artery Disease
Authors: Donal N. Reddan, Lynda Anne Szczech, Robert H. Tuttle, Linda K. Shaw, Robert H. Jones, Steve J. Schwab, Mark Stafford Smith, Robert M. Califf, Daniel B. Mark, William F. Owen
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Cardiovascular disease is an important cause of mortality among patients with chronic kidney disease (CKD). This study describes associations between CKD, cardiac revascularization strategies, and mortality among patients with CKD and cardiovascular disease. All patients undergoing cardiac catheterization at Duke University Medical Center (1995 to 2000) with documented stenosis ≥75% of at least one coronary artery and available creatinine data were included. CKD was staged using creatinine clearance (CrCl) derived from the Cockcroft-Gault formula (normal, ≥90 ml/min; mild, 60 to 89 ml/min; moderate, 30 to 59 ml/min; severe, 15 to 29 ml/min). Cox proportional-hazard regression estimated the relationship between clinical variables, including CrCl and percutaneous coronary artery intervention (PCI), coronary artery bypass grafting (CABG), medical management, and patient survival. There were 4584 patients included, and 24% had CrCl <60 ml/min. Each 10-ml/min decrement in CrCl was associated with an increase in mortality (hazard ratio, 1.14; P < 0.0001). CABG was associated with a survival benefit among patients with both normal renal function and patients with CKD compared with medical management. In patients with normal renal function, CABG was not associated with survival benefit over PCI. However, in patients with CKD, CABG was associated with improved survival. PCI was associated with a survival benefit compared with medical management among patients with normal, mildly, and moderately impaired renal function. Among patients with severe CKD, PCI was not associated with improved survival. CABG is associated with greater mortality reduction than PCI in severe CKD. E-mail: [email protected]
Gene Loss and Parallel Evolution Contribute to Species Difference in Flower Color
Authors: S. D. Smith, M. D. Rausher
Journal: Molecular Biology and Evolution (2011)

Although the importance of regulatory and functional sequence evolution in generating species differences has been studied to some extent, much less is known about the role of other types of genomic changes, such as fluctuation in gene copy number. Here, we apply analyses of gene function and expression of anthocyanin pigment pathway genes, as well as cosegregation analyses in backcross populations, to examine the genetic changes involved in the shift from blue to red flowers in Andean Iochroma (Solanaceae). We demonstrate that deletion of a gene coding for an anthocyanin pathway enzyme was necessary for the transition to red floral pigmentation. The downregulation of a second pathway gene was also necessary for the novel flower color, and this regulatory pattern parallels the genetic change in the two other red-flowered species in the sister family Convolvulaceae in which flower color change has been examined genetically. Finally, we document a shift in enzymatic function at a third locus, but the importance of this change in the transition to red flowers depends on the exact order with which the three changes occurred. This study shows that gene inactivation or loss can be involved in the origin of phenotypic differences between species, thereby restricting the possibility of reversion to the ancestral state. It also demonstrates that parallel evolution of red flowers in three different species occurs via a common developmental/regulatory change but by mutations in different genes.
Translating Gene Expression Into Clinical Care: Sarcomas As a Paradigm
Authors: Torsten O. Nielsen, Robert B. West
Journal: Journal of Clinical Oncology (2010)

Whereas most solid tumors are characterized by considerable genetic instability and molecular heterogeneity, sarcomas include many subtypes with very specific underlying molecular events driving oncogenesis. Gene expression profiling and other modern techniques have consequently had particular success in identifying the critical biologic pathways active in specific sarcomas, yielding insights which can be translated into useful diagnostic biomarkers. Public availability of data sets and new sequencing-based technologies will accelerate this process. Molecular studies have also identified oncogenic pathways of particular importance in sarcomas which can be targeted by investigational drugs. Examples include histone deacetylases in translocation-associated sarcomas of young adults, Akt/mammalian target of rapamycin in pleomorphic sarcomas, and macrophage colony-stimulating factor in tenosynovial giant cell tumor. Despite challenges in organization and accrual, future clinical trials of sarcomas need to be designed that take into account specific molecular subtypes as distinct diseases.
Timing of the first variceal hemorrhage in cirrhotic patients: Prospective evaluation of Doppler flowmetry, endoscopy and clinical parameters
Authors: S SIRINGO
Journal: Hepatology (1994)

We followed 87 cirrhotic patients with esophageal varices and without previous hemorrhage for a mean period of 24 mo to prospectively evaluate the occurrence of variceal bleeding within (early) or after (late) 6 mo from entry and the contribution of portal Doppler ultrasound parameters to the prediction of early and late hemorrhage. Clinical, biochemical, endoscopic and portal Doppler ultrasound parameters were recorded at entry. Variceal bleeding occurred in 22 patients (25.3%). Nine (40.9%) bled within the first 6 mo. Cox regression analysis identified variceal size, cherry-red spots, serum bilirubin and congestion index of the portal vein (the ratio of portal vein [cross-sectional area] and portal blood flow velocity) as the only independent predictors of first variceal hemorrhage. Discriminant analysis was used to find the prognostic index cut off points to identify patients who bled within 6 mo (prognostic group 1) or after 6 mo (prognostic group 2) or remained free of bleeding (prognostic group 3). The cumulative proportion of patients correctly classified was 73% in prognostic group 1, 47% in prognostic group 2 and more than 80% in prognostic group 3. The addition of Doppler ultrasound flowmetry to clinical, biochemical and endoscopic parameter only improved the classification of patients with early bleeding.
Binding of collagen alpha1 chains to human platelets.
Authors: T M Chiang, E H Beachey, A H Kang
Journal: Journal of Clinical Investigation (1977)

We previously reported that purified alpha1 chains of type 1 chick skin collagen induce platelet aggregation. We now describe immunological and biochemical evidence that the peptide binds to intact platelets as an early event in the induction of platelet aggregation and the release reaction. Antibody against alpha1 (I) was obtained by immunizing rabbits with complete Freund's adjuvant mixed with purified alpha1. Immunofluorescence studies showed that alpha1(I)-treated platelets exhibited strong immunofluorescence. The intensity of fluorescence was markedly decreased by the pretreatment of platelets with alpha1-CB5 and glucosylgalactosylhydroxylysine. Dose-response curves of platelet aggregation induced by alpha1 and the binding of alpha1 by washed intact platelets are correlated. The biochemical studies showed that the binding of the alpha1 chain to washed intact platelets was platelet concentration and temperature dependent, and that it reached a maximum in 10 min. The process was reversible and specific, with an association constant of 1.7 muM. The inhibitor of alpha1-induced platelet aggregation, glucosylgalactosyl hydroxylysine, inhibited the alpha1 binding. These results suggest that alpha1(I) chains bind to specific receptor site(s) on platelet membranes to trigger aggregation and the release reaction.
Not Born Equal: Increased Rate Asymmetry in Relocated and Retrotransposed Rodent Gene Duplicates
Authors: B. P. Cusack, K. H. Wolfe
Journal: Molecular Biology and Evolution (2006)

Duplicated genes frequently evolve at different rates. This asymmetry is evidence of natural selection's ability to discriminate between the 2 copies, subjecting them to different levels of purifying selection or even permitting adaptive evolution of one or both copies. However, if gene duplication creates pairs of protein-coding sequences that are initially identical, this raises the question of how selection tells the 2 copies apart. Here, we investigated asymmetric sequence divergence of recently duplicated genes in rodents and related this to 2 possible sources of such asymmetry: gene relocation as a consequence of duplication and retrotransposition as a mechanism of gene duplication. We found that most young rodent duplicates that have been relocated were created by retrotransposition. The degree of rate asymmetry in gene pairs where one copy has been relocated (either by retrotransposition or DNA-based duplication) is greater than in pairs formed by local DNA-based duplication events. Furthermore, by considering the direction of transposition for distant duplicates, we found a consistent tendency for retrogenes to undergo accelerated protein evolution relative to their static paralogs, whereas DNA-based transpositions showed no such tendency. Finally, we demonstrate that the faster sequence evolution of retrogenes correlates with the profound alteration of their expression pattern that is precipitated by retrotransposition.
The development of arthritis and antinuclear antibodies correlate with serum 25-hydroxyvitamin D levels in patients with leprosy
Authors: Sandra L E Ribeiro, Helena L A Pereira, Cristovao Luis Mangueira, Carlos E S Ferreira, Eliane Rosseto, Morton Scheinberg
Journal: Annals of the Rheumatic Diseases (2012)

Leprosy, a chronic granulomatous infection, presents with cutaneous and neurological manifestations. Musculoskeletal involvement, though the third most common manifestation, is underdiagnosed.1 ,2 In its natural history, other immune manifestations besides articular manifestations may be present, such as the presence of autoantibodies.3 ,4 There is evidence that vitamin D influences the activity of immune-mediated diseases, particularly autoimmune diseases.5 ,6 Amazon is a state in the northern part of Brazil where the disease is endemic. It has a high level of sunshine, so a low prevalence of vitamin D insufficiency would be expected. In this study we looked at the serum vitamin D …
Prostate-Restricted Replicative Adenovirus Expressing Human Endostatin-Angiostatin Fusion Gene Exhibiting Dramatic Antitumor Efficacy
Authors: Xiong Li, You-Hong Liu, Sang-Jin Lee, Thomas A. Gardner, Meei-Huey Jeng, Chinghai Kao
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Our previous studies coadministering a replication-deficient adenovirus expressing endostatin and angiostatin fusion gene (EndoAngio) and a prostate-restricted, replication-competent adenovirus (PRRA) showed dramatic antitumor efficacy. This study integrated EndoAngio with an improved PRRA vector to make a single antiangiogenic PRRA, thereby exerting a similarly dramatic antitumor effect with feasibility for future clinical trials. Experimental Design: We developed an antiangiogenic PRRA with structural improvements. The antitumor efficacy of EndoAngio-PRRA was evaluated in prostate-specific antigen/prostate-specific membrane antigen (PSA/PSMA)-positive, androgen-independent CWR22rv tumor models. The tumor vasculature and cell morphology were observed by dual-photon microscopy. The antiangiogenic effect of EndoAngio delivered by PRRA and the killing activity of EndoAngio-PRRA were evaluated in vitro. Virus-inactivated conditioned media from virus-infected PSA/PSMA-positive cells were tested for apoptosis induction in prostate cancer cells. Results: Our novel EndoAngio-PRRA is a strong antiangiogenic and antitumor agent. Nine of 10 CWR22rv tumors treated by EndoAngio-PRRA completely regressed, with 1 tumor remaining in a dormant status for 26 weeks after treatment. Dual-photon microscopy revealed that EndoAngio-PRRA not only inhibited the development of tumor vasculature but also induced apoptosis in tumor cells. Subsequent in vitro study indicated that EndoAngio-PRRA exhibited stronger tumor-specific killing activity than enhanced green fluorescent protein-PRRA, which expresses enhanced green fluorescent protein instead of EndoAngio. Virus-inactivated conditioned medium from EndoAngio-PRRA–infected PSA/PSMA-positive cells induced apoptosis in C4-2 and CWR22rv cells. Conclusions: EndoAngio-PRRA uniquely combines three distinct antitumor effects to eliminate androgen-independent prostate cancer: antiangiogenesis, viral oncolysis, and apoptosis. This novel antiangiogenic PRRA represents a powerful agent feasible for future clinical trials for prostate cancer therapy.
British hospitals and different versions of the Glasgow coma scale: telephone survey
Authors: M. F Wiese
Journal: BMJ (2003)

The Glasgow coma scale is a clinical scoring system for objectively assessing how conscious a patient is. Although limited for predicting functional outcome,1 the scale is useful when making decisions about management in the acute setting, particularly for patients with traumatic brain injuries. Patients who score < 15 need imaging or observation, and patients with scores < 9 need to be promptly considered for definitive airways management.

The original Glasgow coma scale, published in 1974, had 14 points.2 Two years later, its authors introduced a distinction between “normal” and “abnormal” flexion (withdrawal to pain and decorticate response) increasing the “best motor response” item by one point.3 This revised scale is central to important clinical guidelines and has been the accepted …