tbuckley/cabot-search huggingface dataset:
Vaccinia Virus Induces Programmed Necrosis in Ovarian Cancer Cells
Authors: Lynsey M Whilding, Kyra M Archibald, Hagen Kulbe, Frances R Balkwill, Daniel Öberg, Iain A McNeish
Journal: Molecular Therapy (2013)

The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-α, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events. The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-α, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events.
Disseminated toxoplasmosis in a severely immunodeficient patient: Demonstration of cysts in bone marrow smears
Authors: Mirella Soulier‐Lauper, Gilbert Zulian, Gianpaolo Pizzolato, Jeremy Cox, Claudine Helg, Photis Beris
Journal: American Journal of Hematology (1991)

Abstract A 30‐year‐old woman was treated with unrelated HLA‐compatible bone marrow transplantation for acute myeloid leukemia. Examination of her bone marrow smears because of fever and pancytopenia revealed the presence of Toxoplasma cysts. Although Toxoplasma cysts are rarely found in the bone marrow, bone marrow examination in the immunocompromised patient offers rapid diagnosis of systemic toxoplasmosis.
Exclusion of Genetic Information From the Medical Record
Authors: Robert Klitzman
Journal: JAMA (2010)

Increasingly, physicians and patients face dilemmas of whether to exclude genetic information from medical charts, posing critical challenges for practice, research, policy, and education. Physicians and patients are obtaining more genetic information, yet medical records are rapidly becoming electronic, threatening confidentiality. Tensions thus arise between potential medical benefits vs social risks of including information. Use of genetic testing is rapidly increasing through clinicians and direct-to-consumer marketing. Direct-to-consumer tests may be definitive or show only slightly increased disease probabilities, but with advances may have increasing clinical utility. Several institutions have also discussed including whole genome data in medical records. Genetic discrimination has occurred with α1-antitrypsin deficiency, Huntington disease, and other mutations,1 although the extent remains unclear,2 partly because such discrimination can be subtle or difficult to prove. Patients may be passed over for promotion or marginalized, but not fired.3

The Health Insurance Portability and Accountability Act (HIPAA) protects medical information in certain contexts and the 2008 Genetic Information Nondiscrimination Act (GINA) protects genetic test results in the absence of symptoms, but these laws do not prevent discrimination in many realms (eg, life, disability, or long-term care insurance). Many patient advocates are concerned that under GINA, discriminating against patients and paying fines may cost companies less than covering them—as racial, sex, and age discrimination continue, despite legislation. Federal health care reforms of 2010 should broaden coverage of preexisting conditions but have yet to be implemented, and advocates are concerned that reforms might simply raise premiums.
Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle
Authors: Charlotte Ling, Pernille Poulsen, Stina Simonsson, Tina Rönn, Johan Holmkvist, Peter Almgren, Per Hagert, Emma Nilsson, Amanda G. Mabey, Peter Nilsson, Allan Vaag, Leif Groop
Journal: Journal of Clinical Investigation (2007)

Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance.
Benefit and Harm Associated with Screening for Breast Cancer
Authors: Harold C. Sox
Journal: New England Journal of Medicine (1998)

Despite many high-quality randomized trials, the balance of harm and benefit attributable to breast-cancer screening is not known for women 40 to 49 years of age. In this issue of the Journal, Elmore et al.1 describe a high rate of false positive results of such screening. Over a period of 10 years, nearly one third of the women screened had at least one false positive mammogram or clinical breast examination. Physicians must integrate this information into their approach to helping women decide about breast-cancer screening.Periodic screening invites repeated exposure to the possibility of a false positive result, as occurs . . .
INFLUENCE OF PREGNANCY, LACTATION, GROWTH, AND AGING ON NUTRITIONAL PROCESSES
Authors: Tom D. Spies
Journal: JAMA (1953)

Disease is as old as living matter. From time eternal, man has sought means of easing his pain, relieving his disabilities, and discriminating between the foods that are good for him and those that are not. His progress has been made through a process of trial and error. It is the physician's duty to devise ways and means of aiding him. In this report I will discuss how the physician can best make use of his opportunity. The cells of the human body, like all other living things, must adapt, grow, and reproduce. By the time one has become a mature adult, he has had perhaps thousands of illnesses, large and small, which he has overcome. If the investigator is to aid the practicing physician, the work they do must be integrated, dedicated to the truth, and applied toward preventing disease and maintaining health. In the present-day practice of medicine
Enrichment of the rare CD4+ γδ T-cell subset in patients with atypical CD3δ deficiency
Authors: Beatriz Garcillán, Marina S. Mazariegos, Paul Fisch, Pieter C. Res, Miguel Muñoz-Ruiz, Juana Gil, Eduardo López-Granados, Edgar Fernández-Malavé, José R. Regueiro
Journal: Journal of Allergy and Clinical Immunology (2013)
Physical and Psychologic Factors in Glue Sniffing
Authors: Oliver N. Massengale, Helen H. Glaser, Robert E. LeLievre, J. B. Dodds, Mary E. Klogk
Journal: New England Journal of Medicine (1963)

DELIBERATE inhalation of the solvent vapors of model-building cements has become an increasingly common practice among older children and adolescents during the past three years. A detailed description of this problem, including the methods employed and sensations induced, was reported in a previous communication.1 Although considerable speculation concerning the possible physical effects of this practice has appeared in medical publications, as well as in the popular press, we know of no published accounts in this country of systematic investigation of this problem. One such article, however, has appeared in the Swedish literature.2 Case MaterialIn an attempt to define further . . .
Evaluation of <scp>d</scp>-Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis
Authors: Saleha B. Vuyyuri, Daniel A. Hamstra, Divya Khanna, Christin A. Hamilton, Sonja M. Markwart, Kathleen C.M. Campbell, Prasad Sunkara, Brian D. Ross, Alnawaz Rehemtulla
Journal: Clinical Cancer Research (2008)

Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. D-Methionine (D-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults.We evaluated if D-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice.Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P<0.05) whereas it did not confer a similar protection on transformed tumor cells. D-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6+/-0.15). D-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by D-Met treatment. Pharmacokinetics following administration of a liquid suspension of D-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral D-Met doses between 200 and 500 mg/kg (P<0.0003).D-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of D-Met to protect from oral mucositis are warranted.
The relation of body weight to side effects associated with oral contraceptives.
Authors: P P Talwar, G S Berger
Journal: BMJ (1977)

certain, and indeed it is unlikely, that the blood concentrations were constant throughout the six months before their determination.We were, however, careful to exclude patients whose documentation was inadequate, and the picture that emerged is consistent with the findings of our prospective study" and reinforces our view that many patients are unnecessarily treated with two (or more) drugs when one, guided by blood level monitoring, would do.In conclusion, we suggest the following policy for treating new patients with any one type of seizure.The patient should be treated with one drug, which should be gradually increased in dose until seizures are controlled or, if seizures are continuing, until the blood drug concentration is at the higher end of the optimum range.Only when seizures continue despite an optimum blood concentration is it justifiable to consider adding a second drug (the possibility of an alternative drug should also be considered).In this way we believe that much unnecessary polypharmacy, with its attendant hazards, could be avoided.The fact that only 104 of our 276 patients were taking two or more drugs reflects the introduction of this policy in this clinic in the past three years.We are grateful to Mr L Vydelingum and Mr M Laundy for measuring the serum anticonvulsant levels; to the MRC, Parke-Davis, and Geigy for financial support; and to our colleagues in the neurology clinic for their help and advice.
Website of the week: Gene therapy
Authors: B. Twisselmann
Journal: BMJ (2003)

A treatment for cystic fibrosis. A cure for AIDS. The end of cancer. In the early 1990s gene therapy, the subject of the review on this page by Alastair Kent, seemed a panacea to all that ailed mankind (www.pbs.org/saf/1202/features/genetherapy.htm). Scientists had learnt how to insert healthy genes into unhealthy people. Those healthy genes would either replace the bad genes that cause diseases such as cystic fibrosis, sickle cell anaemia, and haemophilia or stimulate the body's own immune system to rid itself of HIV and some forms of cancer.

But the death, in 1999, of US teenager Jesse Gelsinger after participating in a clinical trial sent shockwaves through the scientific and research community. The number of websites devoted to that incident are testimony to how profound an effect Jesse's death had (see, for example www.cancer-coverup.com/cancer-horror-stories/jesse-gelsinger-02.html and www.humangenetherapy.com/french/history/biotech.pdf).

As the Human Genome Project (www.ornl.gov/hgmis/medicine/genetherapy.html) points out, gene therapy is still in its infancy, and current gene therapy is primarily experimental, with most human clinical trials only in the research stages. Information on genetic disorders in the United Kingdom is available from the Genetic Interest Group (www.gig.org.uk/) and gene therapy in particular from the Gene Therapy Advisory Committee (www.doh.gov.uk/genetics/gtac/index.htm).

For a European perspective, visit the site of the European Society of Gene Therapy (www.esgt.org/). Apart from promoting basic and clinical research in gene therapy, the society's aims are to promote education and the exchange of information and technology related to gene transfer and therapy and to serve as a professional adviser to the community and to the regulatory bodies in Europe.
Effects of BG9719 (CVT-124), an A1-Adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure
Authors: Stephen S Gottlieb, Sandra L Skettino, Andrew Wolff, Evan Beckman, Michael L Fisher, Ronald Freudenberger, Tim Gladwell, Joanne Marshall, Michelle Cines, Donald Bennett, Elizabeth B Liittschwager
Journal: Journal of the American College of Cardiology (2000)
MYOCARDIAL INFARCT HETEROGENEITY ASSESSED BY LATE GADOLINIUM-ENHANCED CARDIOVASCULAR MAGNETIC RESONANCE (LGE-CMR) IS ASSOCIATED WITH THE DEVELOPMENT OF VENTRICULAR TACHYCARDIAS AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Lourens Robbers, Ronak Delewi, Michiel Kemme, Robin Nijveldt, Aernout Beek, Alexander Hirsch, Anja Van Der Laan, Pieter van der Vleuten, Jan Piek, Felix Zijlstra, Albert van Rossum
Journal: Journal of the American College of Cardiology (2012)
Enhancement of the impaired autologous mixed leukocyte reaction in patients with systemic lupus erythematosus.
Authors: M K Crow
Journal: Journal of Clinical Investigation (1985)

The cellular basis of the impaired autologous mixed leukocyte reaction (AMLR) in patients with systemic lupus erythematosus (SLE) was investigated. Non-T cells from normal subjects and from SLE patients were fractionated into low and high density subpopulations. SLE patients were found to have an increased proportion of low density to high density non-T cells when compared to normal subjects. Although normal low-density non-T cells were highly enriched in AMLR stimulatory capacity, SLE low-density non-T cells induced minimal proliferation by autologous T cells. Brief incubation of SLE non-T cells with phorbol myristate acetate or formalin-treated Staphylococcus aureus resulted in marked augmentation of the capacity of those non-T cells to stimulate an AMLR, although the magnitude of the activated non-T cell-induced AMLR did not achieve that observed in normal subjects. No significant alterations in the expression of Ia molecules on the surface of the non-T cells were detected after in vitro activation. These experiments support the hypothesis that the impaired capacity of SLE T lymphocytes to proliferate in response to autologous non-T cells may in part represent a failure of SLE non-T cells to present an appropriate stimulus for the generation of a T cell response.
Career guidance for doctors
Authors: D. Carnall
Journal: BMJ (1997)

British doctors may not be deserting the profession,1 but there is no doubt of the disillusionment that currently afflicts them.2 If morale is the difference between current perceptions and future expectations, it is reasonable to suppose that better information, advice, and counselling about career and employment would help doctors to narrow that gap. Yet career advice for doctors can be hard to come by. At medical school students often do not have access to university career services3 and, even when they do, do not always use them.4 After graduation, sources of advice are much less clear. The BMJ 's Career Focus section, one year old this week, provides a forum for gathering and channelling this information. It attempts to address the paradox that, although doctors are the most expensive workforce within the NHS, little information has been available for them to make informed decisions about their careers.

The diversity of sources of information on doctors' careers is part of the problem: much of the relevant information exists in the grey literature …
Treatment of Breast Cancer
Authors: George B. Hutchison
Journal: JAMA (1969)

Getzen and co-authors in a communication entitled  Treatment of Primary Breast Cancer1conclude that radiation significantly decreases survival when used following radical mastectomy in the primary management of carcinoma of the breast. The conclusion rests on two bodies of data: a group of 215 patients treated at the San Diego Naval Hospital and a group of 18,727 patients at a variety of institutions and reported to the End Results Group of the National Cancer Institute.  The End Results Group have previously cautioned against the use of their data for evaluation of therapy. They have written relative to their own data,  ... all observed differences... obtained with different therapies must be evaluated in the light of the way the data are collected and the limitations of the available data. No firm conclusions regarding the relative efficacy of different modalities of treatment are possible. The punched cards make possible the characterization
Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress
Authors: Marianne B Müller, Stephan Zimmermann, Inge Sillaber, Thomas P Hagemeyer, Jan M Deussing, Peter Timpl, Michael S D Kormann, Susanne K Droste, Ralf Kühn, Johannes M H M Reul, Florian Holsboer, Wolfgang Wurst
Journal: Nature Neuroscience (2003)
The prevalence of plant food allergies: A systematic review
Authors: Laurian Zuidmeer, Klaus Goldhahn, Roberto J. Rona, David Gislason, Charlotte Madsen, Colin Summers, Eva Sodergren, Jorgen Dahlstrom, Titia Lindner, Sigurveig T. Sigurdardottir, Doreen McBride, Thomas Keil
Journal: Journal of Allergy and Clinical Immunology (2008)
THE PROGNOSTIC SIGNIFICANCE OF THE INFLAMMATORY BIOMARKER YKL-40 IN RELATION TO MORTALITY IN ALL-COMERS. A FOLLOW-UP STUDY AFTER 11 YEARS
Authors: Jens Kastrup, Naja Mygind, Kasper Iversen, Lars Kober, Jens P. G&oslash;tze, Henrik Nielsen, S&oslash;ren Boesgaard, Morten Bay, Julia Johansen, Olav W. Nielsen, Vibeke Kirk
Journal: Journal of the American College of Cardiology (2012)
Evidence for a Role of Free Fatty Acids in the Regulation of Somatostatin Secretion in Normal and Alloxan Diabetic Dogs
Authors: Taro Wasada, Barbara Howard, Richard E. Dobbs, Roger H. Unger
Journal: Journal of Clinical Investigation (1980)

To investigate the effect of acute elevation of plasma free fatty acids (FFA) on the secretion of splanchnic somatostatin-like immunoreactivity (SLI), the peripheral venous, pancreatic, and gastric venous effluent levels of SLI were measured in normal and chronic alloxan diabetic dogs before and after the infusion of a fat emulsion supplemented with heparin. In normal conscious dogs heparin injected during the infusion of a fat emulsion elevated FFA levels from a mean (±SE) base-line level of 0.7±0.1 meq/liter to a peak value of 1.5±0.1 meq/liter (P < 0.001) and plasma SLI rose from a mean (±SE) base-line value of 145±7 pg/ml to a peak of 253±44 pg/ml (P < 0.05). Neither the infusion of glycerol, of fat emulsion without heparin, of heparin alone nor of saline itself had an effect on either the plasma level of FFA or SLI. In another group of anesthetized dogs with surgically implanted catheters the administration of fat emulsion plus heparin was accompanied by more than a two-fold rise in the concentration of SLI in the venous effluent of the pancreas and of the gastric fundus and antrum in association with an elevation of FFA levels. In a group of conscious diabetic dogs fat emulsion plus heparin raised FFA from a mean base-line level of 1.2±0.2 to 1.6±0.3 meq/liter (P < 0.05) and SLI rose from a mean base-line level of 185±9 pg/ml to a peak value of 310±44 pg/ml (P < 0.01). Although SLI levels were significantly greater than in normal dogs at several time points after the rise in FFA, the magnitude of the increment in diabetic dogs did not differ from normal. These results demonstrate that a rise in FFA levels is a potent stimulus for SLI secretion from the pancreas and stomach and raise the possibility that FFA is an important physiological regulator of SLI secretion.