tbuckley/cabot-search huggingface dataset:
Homozygous Premature Truncation of the HERG Protein
Authors: Theo Hoorntje, Marielle Alders, Peter van Tintelen, Karin van der Lip, Narayanswami Sreeram, Allard van der Wal, Marcel Mannens, Arthur Wilde
Journal: Circulation (1999)

Background —In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K + channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits “loss of function.” HERG, which is involved in LQT2, is the gene encoding the rapid component of the delayed rectifier, I Kr . Methods and Results —In a consanguineous family, a stillbirth was followed by the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, β-blocker therapy was begun, and a pacemaker was implanted. She developed well and remained symptom-free for 1.5 years. In the index patient, we identified a duplication of bp 558 to 600 in exon 4 of HERG on both alleles. This will result in a frameshift and a premature stop codon before the S1 domain of the HERG protein. Because it is present on both alleles, no functional I Kr is anticipated. The same mutation was found heterozygously in both parents and homozygously in the stillborn brother. Conclusions —It is concluded that absence of I Kr gives rise to a severe cardiac phenotype, with no indication of malfunction of any other organ.
Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in a<i>Pten</i>-Deficient Mouse Model of Prostate Cancer
Authors: Weisheng Zhang, Joe Zhu, Clay L. Efferson, Chris Ware, Jennifer Tammam, Minilik Angagaw, Jason Laskey, Kimberly A. Bettano, Shailaja Kasibhatla, John F. Reilly, Cyrille Sur, Pradip K. Majumder
Journal: Cancer Research (2009)

Androgen receptors have been shown to play a critical role in prostate cancer. We used ultrasound imaging techniques to track tumor response to antiandrogen and rapamycin treatment in a prostate-specific Pten-deleted mouse model of cancer. Depletion of androgens by either surgical or chemical castration significantly inhibited tumor growth progression without altering the activation of Akt and mammalian target of rapamycin (mTOR). We also showed for the first time that targeting mTOR along with antiandrogen treatment exhibited additive antitumor effects in vivo when compared with single agents. Our preclinical data suggest that combination of antiandrogens with mTOR inhibitors might be more effective in treating androgen-dependent prostate cancer patients.
Endogenous lipid mediators in the resolution of airway inflammation
Authors: O. Haworth, B. D. Levy
Journal: European Respiratory Journal (2007)

Acute inflammation in the lung is fundamentally important to host defence, but chronic or excessive inflammation leads to several common respiratory diseases, including asthma and acute respiratory distress syndrome. The resolution of inflammation is an active process. In health, events at the onset of acute inflammation establish biosynthetic circuits for specific chemical mediators that later serve as agonists to orchestrate a return to tissue homeostasis. In addition to an overabundance of pro-inflammatory stimuli, pathological inflammation can also result from defects in resolution signalling. The understanding of anti-inflammatory, pro-resolution molecules and their counter-regulatory signalling pathways is providing new insights into the molecular pathophysiology of lung disease and opportunities for the design of therapeutic strategies. In the present review, the growing family of lipid mediators of resolution is examined, including lipoxins, resolvins, protectins, cyclopentenones and presqualene diphosphate. Roles are uncovered for these compounds, or their structural analogues, in regulating airway inflammation.
Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study
Authors: Matthew Bates, Justin O'Grady, Markus Maeurer, John Tembo, Lophina Chilukutu, Chishala Chabala, Richard Kasonde, Peter Mulota, Judith Mzyece, Mumba Chomba, Lukundo Mukonda, Maxwell Mumba, Nathan Kapata, Andrea Rachow, Petra Clowes, Michael Hoelscher, Peter Mwaba, Alimuddin Zumla
Journal: The Lancet Infectious Diseases (2012)
Integration of Genotypic and Phenotypic Screening Reveals Molecular Mediators of Melanoma–Stromal Interaction
Authors: Megan J. Stine, C. Joanne Wang, Whei F. Moriarty, Byungwoo Ryu, Raymond Cheong, William H. Westra, Andre Levchenko, Rhoda M. Alani
Journal: Cancer Research (2011)

Tumor-endothelium interactions are critical for tumor survival and metastasis. Melanomas can rapidly metastasize early in tumor progression, but the dependence of this aggressive behavior on tumor-stromal interaction is poorly understood. To probe the mechanisms involved, we developed a heterotypic coculture methodology, allowing simultaneous tracking of genomic and phenotypic changes in interacting tumor and endothelial cells in vitro. We found a dramatic rearrangement of endothelial cell networks into patterns reminiscent of vascular beds, even on plastic and glass. Multiple genes were upregulated in the process, many coding for cell surface and secreted proteins, including Neuropilin-2 (NRP2). A critical role of NRP2 in coordinated cell patterning and growth was confirmed using the coculture system. We conclude that NRP2 represents an important mediator of melanoma-endothelial interactions. Furthermore, the described methodology represents a powerful yet simple system to elucidate heterotypic intercellular interactions mediating diverse physiological and pathological processes.
First patient with MERS in US is improving, but number of cases worldwide doubles in six weeks to 6 May
Authors: O. Dyer
Journal: BMJ (2014)

An American healthcare professional who brought the first case of Middle Eastern respiratory syndrome (MERS) to North America is improving daily and should soon be discharged into home isolation, Indiana health officials said. The man, who worked at a hospital in Riyadh, flew to Chicago via Heathrow airport on 24 April then took a bus to Munster, Indiana. He fell ill three days later.

British and US officials have contacted most of the passengers on the plane and the bus, and testing so far has revealed no transmission. Anne Schuchat, responsible for respiratory diseases at the Centers for Disease Control, told a media briefing that the importation posed a very low risk to the wider community but “we …
Role of capsaicin sensitive nerves in epidermal growth factor effects on gastric mucosal injury and blood flow
Authors: J Y Kang, C H Teng, F C Chen, A Wee
Journal: Gut (1998)

Background —Epidermal growth factor (EGF) and capsaicin protect against experimental gastric mucosal injury. Capsaicin exerts its gastroprotective effect by stimulating afferent neurones leading to release of calcitonin gene related peptide (CGRP) which causes gastric hyperaemia. EGF also causes gastric hyperaemia but whether it acts via capsaicin sensitive neurones is unknown. Aims —To assess the influence of: (1) capsaicin desensitisation on EGF effects on gastric mucosal injury and gastric mucosal blood flow; and (2) close arterial infusion of hCGRP 8–37 , a CGRP antagonist, on EGF effects on gastric mucosal blood flow. Methods —The absolute ethanol induced gastric mucosal injury model in the rat was used. Gastric mucosal damage was assessed by planimetry and light microscopy. Gastric mucosal blood flow was measured by laser Doppler flowmetry in a gastric chamber preparation. Results —Capsaicin desensitisation abolished the gastroprotective and gastric hyperaemic effects of EGF. Close arterial infusion of hCGRP 8–37 antagonised the hyperaemic effect of both capsaicin and EGF. Conclusion —Results show that EGF may exert its gastroprotective and gastric hyperaemic effects via capsaicin sensitive afferent neurones.
Association between maternal age at childbirth and child and adult outcomes in the offspring: a prospective study in five low-income and middle-income countries (COHORTS collaboration)
Authors: Caroline H D Fall, Harshpal Singh Sachdev, Clive Osmond, Maria Clara Restrepo-Mendez, Cesar Victora, Reynaldo Martorell, Aryeh D Stein, Shikha Sinha, Nikhil Tandon, Linda Adair, Isabelita Bas, Shane Norris, Linda M Richter
Journal: The Lancet Global Health (2015)

Both young and advanced maternal age is associated with adverse birth and child outcomes. Few studies have examined these associations in low-income and middle-income countries (LMICs) and none have studied adult outcomes in the offspring. We aimed to examine both child and adult outcomes in five LMICs.In this prospective study, we pooled data from COHORTS (Consortium for Health Orientated Research in Transitioning Societies)-a collaboration of five birth cohorts from LMICs (Brazil, Guatemala, India, the Philippines, and South Africa), in which mothers were recruited before or during pregnancy, and the children followed up to adulthood. We examined associations between maternal age and offspring birthweight, gestational age at birth, height-for-age and weight-for-height Z scores in childhood, attained schooling, and adult height, body composition (body-mass index, waist circumference, fat, and lean mass), and cardiometabolic risk factors (blood pressure and fasting plasma glucose concentration), along with binary variables derived from these. Analyses were unadjusted and adjusted for maternal socioeconomic status, height and parity, and breastfeeding duration.We obtained data for 22 188 mothers from the five cohorts, enrolment into which took place at various times between 1969 and 1989. Data for maternal age and at least one outcome were available for 19 403 offspring (87%). In unadjusted analyses, younger (≤19 years) and older (≥35 years) maternal age were associated with lower birthweight, gestational age, child nutritional status, and schooling. After adjustment, associations with younger maternal age remained for low birthweight (odds ratio [OR] 1·18 (95% CI 1·02-1·36)], preterm birth (1·26 [1·03-1·53]), 2-year stunting (1·46 [1·25-1·70]), and failure to complete secondary schooling (1·38 [1·18-1·62]) compared with mothers aged 20-24 years. After adjustment, older maternal age remained associated with increased risk of preterm birth (OR 1·33 [95% CI 1·05-1·67]), but children of older mothers had less 2-year stunting (0·64 [0·54-0·77]) and failure to complete secondary schooling (0·59 [0·48-0·71]) than did those with mothers aged 20-24 years. Offspring of both younger and older mothers had higher adult fasting glucose concentrations (roughly 0·05 mmol/L).Children of young mothers in LMICs are disadvantaged at birth and in childhood nutrition and schooling. Efforts to prevent early childbearing should be strengthened. After adjustment for confounders, children of older mothers have advantages in nutritional status and schooling. Extremes of maternal age could be associated with disturbed offspring glucose metabolism.Wellcome Trust and the Bill & Melinda Gates Foundation.
Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor
Authors: Jie Hong Hu, Phanith Touch, Jingwan Zhang, Hao Wei, Shihui Liu, Ida K. Lund, Gunilla Høyer-Hansen, David A. Dichek
Journal: Cardiovascular Research (2015)

Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation. SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22–29%) and oil-red-O-positive lesion area (36–42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6–10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity. Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis.
Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case–control study (EuroSCAR)
Authors: A. Sidoroff, A. Dunant, C. Viboud, S. Halevy, J.N. Bouwes Bavinck, L. Naldi, M. Mockenhaupt, J-P. Fagot, J-C. Roujeau
Journal: British Journal of Dermatology (2007)

Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs.To evaluate the risk for different drugs of causing AGEP.A multinational case-control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls. Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26-infinity), ampicillin/amoxicillin (CI 10-infinity), quinolones (CI 8.5-infinity), (hydroxy)chloroquine (CI 8-infinity), anti-infective sulphonamides (CI 7.1-infinity), terbinafine (CI 7.1-infinity) and diltiazem (CI 5.0-infinity). No significant risk was found for infections and a personal or family history of psoriasis (CI 0.7-2.2).Medications associated with AGEP differ from those associated with Stevens-Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.
An Anti–Transforming Growth Factor β Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments
Authors: Jeong-Seok Nam, Masaki Terabe, Mizuko Mamura, Mi-Jin Kang, Helen Chae, Christina Stuelten, Ethan Kohn, Binwu Tang, Helen Sabzevari, Miriam R. Anver, Scott Lawrence, David Danielpour, Scott Lonning, Jay A. Berzofsky, Lalage M. Wakefield
Journal: Cancer Research (2008)

Overexpression of transforming growth factor beta (TGF-beta) is frequently associated with metastasis and poor prognosis, and TGF-beta antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti-TGF-beta antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1gamma) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-beta expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-beta antibodies reverse this effect, and the absence of a major effect of TGF-beta antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications.
Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.
Authors: T Matsubara, R Saura, K Hirohata, M Ziff
Journal: Journal of Clinical Investigation (1989)

To investigate the effects of D-penicillamine (D-Pen) on angiogenesis, we have studied the effects of this drug on in vitro proliferation of human endothelial cells (EC) and in vivo corneal neovascularization. D-Pen, in the presence of copper sulfate, suppressed tritiated thymidine ([3H]TdR) incorporation into EC in a dose-dependent manner. Significant inhibition was observed with D-Pen concentrations attainable in the serum and tissues of treated patients. Neither D-Pen nor copper ion alone significantly affected [3H]TdR incorporation into EC. The inhibition by D-Pen and copper was blocked by catalase (CAT) or horseradish peroxidase but not by boiled CAT or SOD. When rabbits were daily injected intravenously with D-Pen at the per kilogram dosage administered to rheumatoid patients, neovascularization as quantitated by the proliferation of corneal new blood vessels was significantly inhibited. These results suggest that hydrogen peroxide generated by D-Pen and copper exerts a pronounced antiangiogenic effect through inhibition of EC proliferation. It is, therefore, considered that D-Pen may suppress rheumatoid synovitis by reducing the number of small blood vessels available for the emigration of chronic inflammatory cells, and the proliferation of the synovial tissue.
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Authors: Oleg Butovsky, Mark P Jedrychowski, Craig S Moore, Ron Cialic, Amanda J Lanser, Galina Gabriely, Thomas Koeglsperger, Ben Dake, Pauline M Wu, Camille E Doykan, Zain Fanek, LiPing Liu, Zhuoxun Chen, Jeffrey D Rothstein, Richard M Ransohoff, Steven P Gygi, Jack P Antel, Howard L Weiner
Journal: Nature Neuroscience (2013)
Soviet Medical Research: Some Recent Advances and Future Plans
Authors: A Shelokoy
Journal: Annual Review of Medicine (1958)

s of Biological Sciences and the greatly expanded coverage of Soviet literature by both Biological Abstracts and Chemical Abstracts. Inter­ national Abstracts of Biological Sciences is a new journal which devotes considerable space to Russian articles, while Excerpta Medica now issues a separate periodical journal entitled Abstracts of Soviet Medicine. The vigorous activities on the part of Western scientific circles are eagerly supplemented by apparent efforts of the Russian journals to bring their contents to the attention of non-Soviet readers. A number of Soviet journals in 1957 resumed or initiated the practice of including English language abstracts at the end of each original paper as well as a translated table of contents in parallel with the Russian. The Soviet scientists' expres­ sions of willingness 'and desire to exchange scientific information have been noted by many of the recent medical travelers to Russia. A well-annotated list of references to available first-hand reports on Russian medical research and personalities by Western visitors was recently compiled and is particu­ larly useful in evaluating Soviet literature (4). An interesting study on The Use of Soviet Medical  Information by American Medical Scien­ tists (7) was recently published. It is a useful inquiry into the current attitudes of our research workers and factors determining their utilization of the available journals. The broad scope of Soviet medical research represents the combined productivity of numerous institutes (estimated to number about 500), clinics, and laboratories and generally is not unlike that of the United States or any other large and productive country. An interesting document pro­ viding a glimpse into the hopeful future plans of the Soviets is available for outside inspection. This is the Research Plan of the Academy of Medical Sciences USSR, 1956-60, presented and accepted as part of the sixth over­ all five-year plan at the 20th Congress of the Communist party of the Soviet Union held in Moscow in February, 1956. It was briefly but lucidly reviewed • The first two are published by the Consultants Bureau, New York, and the remaining six by the Pergamon Press of N ew York and London. SOVIET MEDICAL RESEARCH 471 by Paul (5), following his return from Russia as a member of an official U. S. medical mission. The detailed plan emphasizes the need for further investigations in 22 specified fields and includes under each topic not only a brief review of its over-all status but lists the particular problems requiring immediate atten­ tion and even suggests the possible means of experimental approach by the responsible Institutes. Some idea of its scope may be gained from a con­ densed outline of the main headings and some of the specific problems men­
Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease
Authors: Helene Munyentwali, Khedidja Bouachi, Vincent Audard, Philippe Remy, Philippe Lang, Rachid Mojaat, Georges Deschênes, Pierre M. Ronco, Emmanuelle M. Plaisier, Karine Y. Dahan
Journal: Kidney International (2013)
A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice
Authors: Dongeun Huh, Daniel C. Leslie, Benjamin D. Matthews, Jacob P. Fraser, Samuel Jurek, Geraldine A. Hamilton, Kevin S. Thorneloe, Michael Allen McAlexander, Donald E. Ingber
Journal: Science Translational Medicine (2012)

An in vitro model of human pulmonary edema predicts drug toxicity and efficacy previously observed in humans.
Stability of methacholine chloride solutions under different storage conditions over a 9 month period
Authors: RD Hayes, None Beach, DM Rutherford, MR Sim
Journal: European Respiratory Journal (1998)

Methacholine chloride solutions, routinely used for testing bronchial hyperreactivity, have been shown to degrade over time. The data published addressing the optimal conditions for methacholine chloride storage are conflicting and incomplete. This study investigated the effects of a variety of conditions on the stability of methacholine chloride. Methacholine chloride, dissolved in phosphate buffered saline (PBS) or sodium chloride (NaCl) at 50 and 0.39 g x L(-1), was subjected to various light and temperature conditions for 9 months. Methacholine chloride degradation was determined by high performance liquid chromatography, and all solutions underwent bacterial and pH testing. By 9 months, all 50 g x L(-1) solutions of methacholine chloride had degraded by 65+/-0.8%. All 0.39 g x L(-1) solutions in NaCl had degraded by 11.0+/-0.33%. The 0.39 g x L(-1) solutions in PBS which had been frozen, refrigerated or stored at room temperature had degraded by 8.0%, 16.0+/-0.3% and 63.8+/-0.5%, respectively. The pH of methacholine chloride was 7.2 in PBS at 0.39 g x L(-1), 5.8 in PBS at 50 g x L(-1), 3.9 in NaCl at 0.39 and 2.7 in NaCl at 50 g x L(-1). Bacterial contamination was minimal. The results of this study demonstrate that methacholine chloride is more stable at the higher concentration. However, the pH of the more concentrated solutions of methacholine chloride in sodium chloride could cause bronchoconstriction in some subjects. We therefore recommend storing methacholine chloride at 50 g x L(-1) in phosphate-buffered saline.