tbuckley/cabot-search huggingface dataset:
Streptococcal M protein size mutants occur at high frequency within a single strain.
Authors: V A Fischetti, M Jarymowycz, K F Jones, J R Scott
Journal: The Journal of Experimental Medicine (1986)

Streptococcal M protein, the antiphagocytic molecule on the surface of the organism, was previously found to exhibit extensive size heterogeneity between as well as within M serotypes. In this study, methods were devised to isolate M protein size mutants within a laboratory-grown culture. We were able to isolate three independent M protein deletion mutants and one additional mutant, which was derived from the first deletion mutant. We found that these deletion mutants occur at a frequency of approximately 1 in 2 X 10(3) CFUs in culture. Functional studies revealed that the deletion mutants were able to survive as well as the parental strain in human blood. They also had the determinants necessary to absorb opsonic antibodies as well as the parent. Pepsin digestion experiments localized the deletions within the N-terminal half of the M molecule, which is distal to the cell wall surface. This is the region of the molecule in which extensive sequence repeats are found. This is consistent with the suggestion that the size changes may be the result of homologous recombination between the repeat regions in the gene. These results support the idea that strains showing M protein size variation within successive clinical isolates from single patients may be derived from the initial infecting organisms, and are not the result of separate unrelated acquisitions of the same serotype. This size change may be important in the survival of the streptococcus in vivo.
Intrinsic Aerobic Capacity Sets a Divide for Aging and Longevity
Authors: Lauren Gerard Koch, Ole J. Kemi, Nathan Qi, Sean X. Leng, Piter Bijma, Lori J. Gilligan, John E. Wilkinson, Helene Wisløff, Morten A. Høydal, Natale Rolim, Peter M. Abadir, Elizabeth M. van Grevenhof, Godfrey L. Smith, Charles F. Burant, Øyvind Ellingsen, Steven L. Britton, Ulrik Wisløff
Journal: Circulation Research (2011)

Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity.Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis).Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO(2max)), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO(2max), measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca(2+) handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity.These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.
Effect of a Brief Video Intervention on Incident Infection among Patients Attending Sexually Transmitted Disease Clinics
Authors: Lee Warner, Jeffrey D Klausner, Cornelis A Rietmeijer, C. Kevin Malotte, Lydia O'Donnell, Andrew D Margolis, Gregory L Greenwood, Doug Richardson, Shelley Vrungos, Carl R O'Donnell, Craig B Borkowf
Journal: PLoS Medicine (2008)

Sexually transmitted disease (STD) prevention remains a public health priority. Simple, practical interventions to reduce STD incidence that can be easily and inexpensively administered in high-volume clinical settings are needed. We evaluated whether a brief video, which contained STD prevention messages targeted to all patients in the waiting room, reduced acquisition of new infections after that clinic visit.
Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study
Authors: Rustam Al-Shahi Salman, Julie M Hall, Margaret A Horne, Fiona Moultrie, Colin B Josephson, Jo J Bhattacharya, Carl E Counsell, Gordon D Murray, Vakis Papanastassiou, Vaughn Ritchie, Richard C Roberts, Robin J Sellar, Charles P Warlow
Journal: The Lancet Neurology (2012)

BackgroundCerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.MethodsWe undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.Findings139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).InterpretationThe risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.
Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma
Authors: Puya Gharahkhani, Kathryn P Burdon, Rhys Fogarty, Shiwani Sharma, Alex W Hewitt, Sarah Martin, Matthew H Law, Katie Cremin, Jessica N Cooke Bailey, Stephanie J Loomis, Louis R Pasquale, Jonathan L Haines, Michael A Hauser, Ananth C Viswanathan, Peter McGuffin, Fotis Topouzis, Paul J Foster, Stuart L Graham, Robert J Casson, Mark Chehade, Andrew J White, Tiger Zhou, Emmanuelle Souzeau, John Landers, Jude T Fitzgerald, Sonja Klebe, Jonathan B Ruddle, Ivan Goldberg, Paul R Healey, Richard A Mills, Jie Jin Wang, Grant W Montgomery, Nicholas G Martin, Graham Radford-Smith, David C Whiteman, Matthew A Brown, Janey L Wiggs, David A Mackey, Paul Mitchell, Stuart MacGregor, Jamie E Craig
Journal: Nature Genetics (2014)
A Novel Immunoablative Regimen Utilized In The Successful Remission Of Pulmonary Hemorrhage In An Adolescent Female With Systemic Lupus Erythematosus
Authors: Vivian E. Cino, Alexander Constantinescu, Kristina Deeter, Faina Shenderov, Joan Spiro, Gary I. Kleiner
Journal: Journal of Allergy and Clinical Immunology (2014)
Splicing and Transcription Differ between Spore and Intracellular Life Stages in the Parasitic Microsporidia
Authors: E. E. Gill, R. C. H. Lee, N. Corradi, C. J. Grisdale, V. O. Limpright, P. J. Keeling, N. M. Fast
Journal: Molecular Biology and Evolution (2010)

Microsporidia are a diverse group of highly derived fungal relatives that are intracellular parasites of many animals. Both transcription and introns have been shown to be unusual in microsporidia: The complete genome of the human parasite Encephalitozoon cuniculi has only a few very short introns, and two distantly related microsporidian spores have been shown to harbor transcripts encoding several genes that overlap on different strands. However, microsporidia alternate between two life stages: the intracellular proliferative stage and the extracellular and largely metabolically dormant infectious spore. To date, most studies have focused on the spore. Here, we have compared transcription profiles for a number of genes from both life stages of microsporidia and found major differences in both the prevalence of overlapping transcription and splicing. Specifically, spore transcripts in E. cuniculi have longer 5′ untranslated regions, overlap more frequently with upstream genes, and have a significantly higher number of transcription initiation sites compared with intracellular transcripts from the same species. In addition, we demonstrate that splicing occurs exclusively in the intracellular stage and not in spore messenger RNAs (mRNAs) in both E. cuniculi and the distantly related Antonospora locustae. These differences between the microsporidian life stages raise questions about the functional importance of transcripts in the spore. We hypothesize that at least some transcripts in spores are a product of the cell's transition into a dormant state and that these unusual mRNAs could play a structural role rather than an informational one.
DIFFERENTIAL EFFECTS OF EPICARDIAL FAT VOLUME ON CORONARY, AORTIC VALVE AND AORTIC CALCIFICATION
Authors: Ronak Rajani, Damini Dey, Ryo Nakazato, Balaji Tamarappoo, Victor Cheng, Heidi Gransar, Haim Shmilovich, Yuka Otaki, Rine Nakanishi, Nathan Wong, Piotr J. Slomka, Sean W. Hayes, Louise Thomson, John Friedman, Leslee Shaw, Matthew Budoff, Alan Rozanski, Daniel S. Berman
Journal: Journal of the American College of Cardiology (2011)
INHIBITION OF INFLUENZA VIRUS MULTIPLICATION BY ALKYL DERIVATIVES OF BENZIMIDAZOLE
Authors: Igor Tamm, Karl Folkers, Clifford H. Shunk, Dorothea Heyl, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1953)

The degree of inhibition of multiplication of influenza B virus, Lee strain, in membrane cultures in vitro appears to be directly related to the concentration of the inhibitory compounds used in this investigation. With each of the alkyl derivatives of benzimidazole, evidence for such a relationship was obtained in the range between 60 and 90 per cent inhibition of virus multiplication. Alteration of the structure of benzimidazole by substitution of alkyl radicals at various positions in either the benzene or the imidazole ring resulted in diverse differences in the capacity to inhibit influenza virus multiplication in vitro. Minor increases in inhibitory activity resulted when one to three methyl groups were introduced at certain positions in the molecule. Marked increases in inhibitory activity were achieved by more extensive substitution in either the benzene or the imidazole ring. The position and nature of substituent groups appeared to be of decisive importance. Among the more highly active compounds were 2,4,5,6,7-pentamethyl-benzimidazole, 5,6-diethylbenzimidazole, and 2-ethyl-5-methylbenzimidazole. Further extension of the alkyl chain at position 2 caused no significant change in the inhibitory activity of the derivative. The most active compounds studied caused 75 per cent inhibition of Lee virus multiplication in membrane cultures in vitro at concentrations of approximately 0.0002 M. Some of the implications of these findings are discussed.
Common and Complex <i>Notch1</i> Mutations in Chinese Oral Squamous Cell Carcinoma
Authors: Xiaomeng Song, Ronghui Xia, Jiang Li, Zhifeng Long, Hening Ren, Wantao Chen, Li Mao
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To determine Notch1 mutation status in oral squamous cell carcinoma (OSCC) from Chinese population and its potential clinical implications. Experimental Design: Surgically resected OSCC tissues from 51 Chinese patients and 13 head and neck squamous cell carcinoma (HNSCC) cell lines were sequenced for mutations in the entire coding regions of Notch1 and TP53 using a next-generation sequencing platform. Sequences of the genes were also determined in corresponding normal tissues from 46 of the 51 patients. Mutations and their association with clinical parameters were analyzed. Results: Six mutations in Notch1 and 11 mutations in TP53 coding regions were detected in 4 (31%) and 10 (77%) of the 13 HNSCC cell lines, respectively. Forty-two somatic Notch1 mutations, including 7 nonsense mutations and 11 mutations within the domain commonly harboring potential activating mutations in acute lymphoblastic leukemia, were detected in 22 (43%) of the 51 Chinese OSCC tumors. In comparison, 25 somatic TP53 mutations were observed in 21 (41%) of the 51 tumors. Patients whose tumors carried Notch1 mutation had significantly shorter overall and disease-free survivals (P = 0.004 and P = 0.001, respectively, by log-rank test) compared with those whose tumors carried no Notch1 mutation. Multivariate analysis showed that both Notch1 mutation and lymph node metastasis are independent prognostic factors in the patient population (P = 0.001). All 15 patients with both Notch1 mutation and nodal metastasis recurred or metastasized within 2 years after surgery. Conclusions: Notch1 mutation is common in Chinese OSCC and associates with clinical outcomes. The complexity of the mutation spectrum warrants further investigation of Notch1 in Chinese patients with OSCC. Clin Cancer Res; 20(3); 701–10. ©2013 AACR.
Inherited Susceptibility to Colorectal Cancer
Authors: Peter T. Rowley
Journal: Annual Review of Medicine (2005)

The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is due to mutations in the APC gene. HNPCC is due to a mutation in one of at least five mismatch repair genes. Identification of individuals with these conditions is important because colon cancer will occur in ∼80% and onset is early. For FAP, protein truncation testing will identify the vast majority of mutations. For HNPCC, 80%–95% can be identified by microsatellite instability testing. A current U.S. study reports that 12% of consecutive colorectal cancers have high microsatellite instability and that, of this 12%, 25% have detectable mutations of MLH1, MSH2, or MSH6. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, offering of testing to relatives, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance.
Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience.
Authors: P A Meyers, G Heller, J Healey, A Huvos, J Lane, R Marcove, A Applewhite, V Vlamis, G Rosen
Journal: Journal of Clinical Oncology (1992)

PURPOSE Adjuvant chemotherapy improves disease-free survival (DFS) for patients with osteogenic sarcoma (OS). We reviewed our experience with OS to determine prognostic factors, the role of preoperative chemotherapy and subsequent histologic response, and the role of salvage chemotherapy after poor initial response. METHODS From 1975 to 1984, we saw 279 patients with previously untreated OS without metastasis. All patients received intensive chemotherapy and underwent surgical resection of primary tumor. Chemotherapy included high-dose methotrexate; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); and bleomycin, cyclophosphamide, and dactinomycin (BCD). Selected patients also received cisplatin. RESULTS DFS was not affected by use of preoperative chemotherapy versus immediate surgery, by use of limb-sparing surgery versus amputation, age, sex, or dose intensity of chemotherapy. DFS did correlate with serum lactate dehydrogenase (LDH), alkaline phosphatase, primary tumor site, race, and histologic response to preoperative chemotherapy. There was no difference in DFS for patients with a poor histologic response who did or did not receive cisplatin, although patients who did receive cisplatin had a longer time to relapse. The 5-year DFS was 76% for patients aged less than or equal to 21 years who had extremity primary tumor and were treated with the T10 protocol. CONCLUSIONS Intensive chemotherapy can achieve DFS for a high proportion of patients with OS. Although it is a powerful predictor of DFS, histologic response to preoperative chemotherapy cannot be assessed at diagnosis. We have not shown an ability to salvage patients with an unfavorable response. We need to increase the proportion of patients with a favorable response, identify the patients who will have an unfavorable response, and develop novel treatments to salvage poor responders.
Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels
Authors: David J. Rowlands, Mohammad Naimul Islam, Shonit R. Das, Alice Huertas, Sadiqa K. Quadri, Keisuke Horiuchi, Nilufar Inamdar, Memet T. Emin, Jens Lindert, Vadim S. Ten, Sunita Bhattacharya, Jahar Bhattacharya
Journal: Journal of Clinical Investigation (2011)

Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca2+, and the purinergic receptor P2Y2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca2+-dependent increase of mitochondrial H2O2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.
OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells
Authors: Ta-Ming Liu, Yonghua Ling, Jennifer A. Woyach, Kyle Beckwith, Yuh-Ying Yeh, Erin Hertlein, Xiaoli Zhang, Amy Lehman, Farrukh Awan, Jeffrey A. Jones, Leslie A. Andritsos, Kami Maddocks, Jessica MacMurray, Santosh B. Salunke, Ching-Shih Chen, Mitch A. Phelps, John C. Byrd, Amy J. Johnson
Journal: Blood (2014)
The educationalists' standard stranglehold
Authors: A. Levy
Journal: BMJ (2009)

In a norm referenced assessment a candidate’s success or failure depends on the performance of the other examinees. Theoretically, identical scores attained by candidates in sequential high and low achieving year groups might fail one year but pass the next. By contrast, in a criterion referenced exam, a candidate’s achievement is assessed independently of the performance of others by using clearly stated standards related to predetermined learning outcomes. All you need to do is to define with absolute clarity that fine and unwavering line across each skill, every element of knowledge and nuance of attitude that once rated and ordered, differentiates “a doctor” from “not a doctor.” Current dogma is that if you cannot make criterion referencing work you are not trying hard enough.

In a 10 minute data interpretation station our 2008 MB ChB final exam candidates were asked to write a concise discharge summary from a complete set of clinical notes. The assessor—a senior, experienced, and earnest examiner, himself charged with leading a unit in the fourth year of the programme—marked a proportion of …
Violence Prevention and Control Through Environmental Modifications
Authors: Julie Samia Mair, Michael Mair
Journal: Annual Review of Public Health (2003)

Violence traditionally had been considered a problem exclusively within the criminal justice domain, although it is now widely viewed as a public health issue as well. Public health has brought new and complementary tools for understanding and preventing violence. Whereas public health has long recognized the environment as a determinant of disease and injury, it has paid less attention to the environment when considering violence prevention strategies. For several decades though, some criminologists and others have been researching environmental factors in crime prevention. This article aims to discuss the main environmental crime-prevention strategies, provide examples of promising interventions, review public health literature that uses these strategies, discuss what public health can contribute, and suggest public health research to test the hypothesis that violence can be prevented and controlled through environmental modifications.