tbuckley/cabot-search huggingface dataset:
Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study
Authors: Petri Luoma, Atle Melberg, Juha O Rinne, Jyrki A Kaukonen, Nina N Nupponen, Richard M Chalmers, Anders Oldfors, Ilkka Rautakorpi, Leena Peltonen, Kari Majamaa, Hannu Somer, Anu Suomalainen
Journal: The Lancet (2004)
Novel Prognostic Immunohistochemical Biomarker Panel for Estrogen Receptor–Positive Breast Cancer
Authors: Brian Z. Ring, Robert S. Seitz, Rod Beck, William J. Shasteen, Shannon M. Tarr, Maggie C.U. Cheang, Brian J. Yoder, G. Thomas Budd, Torsten O. Nielsen, David G. Hicks, Noel C. Estopinal, Douglas T. Ross
Journal: Journal of Clinical Oncology (2006)

Patients with breast cancer experience progression and respond to treatment in diverse ways, but prognostic and predictive tools for the oncologist are limited. We have used gene expression data to guide the production of hundreds of novel antibody reagents to discover novel diagnostic tools for stratifying carcinoma patients.One hundred forty novel and 23 commercial antisera, selected on their ability to differentially stain tumor samples, were used to stain paraffin blocks from a retrospective breast cancer cohort. Cox proportional hazards and regression tree analysis identified minimal panels of reagents able to predict risk of recurrence. We tested the prognostic association of these prospectively defined algorithms in two independent cohorts.In both validation cohorts, the Kaplan-Meier estimates of recurrence confirmed that both the Cox model using five reagents (p53, NDRG1, CEACAM5, SLC7A5, and HTF9C) and the regression tree model using six reagents (p53, PR, Ki67, NAT1, SLC7A5, and HTF9C) distinguished estrogen receptor (ER)-positive patients with poor outcomes. The Cox model was superior and distinguished patients with poor outcomes from patients with good or moderate outcomes with a hazard ratio of 2.21 (P = .0008) in validation cohort 1 and 1.88 (P = .004) in cohort 2. In multivariable analysis, the calculated risk of recurrence was independent of stage, grade, and lymph node status. A model proposed for ER-negative patients failed validation in the independent cohorts.A panel of five antibodies can significantly improve on traditional prognosticators in predicting outcome for ER-positive breast cancer patients.
Metabolic heterogeneity during preimplantation development: the missing link?
Authors: Daniel R. Brison, Roger G. Sturmey, Henry J. Leese
Journal: Human Reproduction Update (2014)

Most tissues in the body rely on the presence of gap junctions in order to couple their component cells electrically and metabolically via intercellular transport of ions, metabolites and signalling agents. As a result, cells within tissues achieve a high degree of, 'metabolic homogeneity' which enables them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues. Unusually, the developing mammalian preimplantation embryo does not form functional gap junctions until it has divided into 8 or more cells. We discuss the implications of this 'missing link' during the first few days of development for the maintenance of homogeneity between embryonic cells and for the co-ordination of the embryonic response to intrinsic genetic damage and external environmental signals. No systematic review has been carried out. The physiology of preimplantation development and the general nature of gap junctions have been reviewed briefly before examining experimental evidence which addresses the following points: (i) whether there are functional differences between early blastomeres; (ii) when during preimplantation development the embryo is most sensitive to environmental perturbation and (iii) the consequences for early embryos of ablating gap junction formation and function. General conclusions are confounded by species differences, especially in the timing of embryonic genome activation (EGA) and the extent of intrinsic genotypic and phenotypic variation (low in embryos from inbred mice; high in human embryos). Nevertheless, we propose that the absence of gap junctions requires cleavage stage mammalian embryos to behave cell autonomously in a metabolic sense, contributes to their heightened sensitivity to environmental perturbation compared with the later stages of preimplantation development and poses more problems in the early human embryo, where there is a high degree of heterogeneity between the blastomeres. We argue that the legacy of metabolic heterogeneity, in part generated by the absence of gap junctions, is 'rescued' by the onset of apoptosis following EGA. In the context of human-assisted conception, since early embryos lacking gap junctions are more sensitive to environmental stress during cleavage, this would support transfer to the natural environment as early as possible after fertilization.
Late liver-related mortality from complications of transfusion-acquired hepatitis C
Authors: Hiroshi Kamitsukasa, Hideharu Harada, Hideo Tanaka, Michiyasu Yagura, Hajime Tokita, Akira Ohbayashi
Journal: Hepatology (2005)

Although several cohort studies have been reported in individuals with chronic hepatitis C virus (HCV) infection, little is known about liver-related mortality among the elderly. We conducted a cohort study in 302 patients with tuberculosis sequelae who had received a blood transfusion at a young age and had subsequently been treated at a chest clinic. The cohort consisted of 147 patients with antibody to HCV (anti-HCV), of whom 81% were positive for HCV RNA, and 155 without anti-HCV. The cohort was followed for a mean duration of 5.7 years. There were no differences between the two groups in the mean age of the patients at the time of transfusion (31 vs. 34 years) or at the time of entry into the study (65 vs. 66 years). The outcome of 143 patients with, and 145 without, anti-HCV could be traced; 92 (64%) and 82 (57%) had died, respectively. The main cause of death was tuberculosis sequelae in 61 (42%) and 66 (46%) patients, respectively. Eight (6%) of the 143 patients with anti-HCV died of liver disease (hepatocellular carcinoma: seven; rupture of varices: one). The average annual mortality from liver disease from study entry in the patients with anti-HCV was 9.8 per 1,000 person-years. The patients with anti-HCV had a significantly lower cause-specific survival probability for liver disease (92% vs. 100% at 10 years, P < .005). In conclusion, in our study, liver-related mortality appeared to be high among elderly HCV-infected individuals. (HEPATOLOGY 2005;41:819–825.)
Cases of Delirium Tremens Rapidly Cured by Hydrate of Chloral
Authors: J. C. Fletcher
Journal: BMJ (1870)

Towards the end of the month (February 25th), she expressed her- self as feeling better; the paroxysms of headache had been less severe, and she was able to sit up a short time.The strabismus was the same; but ophthalmoscopic examination showed the optic discs less swollen and more defined, and the retina paler.She then left her bed and gradually improved, the pain being less and her health altogether better; and on March 26th, she left off the bromide of potassium.She walked about the ward looking very well, but the strabismus remained in some degree; and, although the face exhibited no paralysis, yet it showed the want of power before mentioned, when the muscles were tested.She occasionally had returns of the pain in the head.She then left the hospital; but was seen on April ioth, free from pain.The case was thus a most difficult one in which to form an accurate diagnosis.
Danger Signaling in Atherosclerosis
Authors: Sebastian Zimmer, Alena Grebe, Eicke Latz
Journal: Circulation Research (2015)

All aspects of the pathogenesis of atherosclerosis are critically influenced by the inflammatory response in vascular plaques. Research in the field of innate immunity from the past 2 decades has uncovered many novel mechanisms elucidating how immune cells sense microbes, tissue damage, and metabolic derangements. Here, we summarize which triggers of innate immunity appear during atherogenesis and by which pathways they can contribute to inflammation in atherosclerotic plaques. The increased understanding gained from studies assessing how immune activation is associated with the pathogenesis of atherosclerosis has provided many novel targets for potential therapeutic intervention. Excitingly, the concept that inflammation may be the core of cardiovascular disease is currently being clinically evaluated and will probably encourage further studies in this area.
Helper Function of Memory CD8+ T Cells: Heterologous CD8+ T Cells Support the Induction of Therapeutic Cancer Immunity
Authors: Yutaro Nakamura, Payal Watchmaker, Julie Urban, Brian Sheridan, Adam Giermasz, Fumihiko Nishimura, Kotaro Sasaki, Rachel Cumberland, Ravikumar Muthuswamy, Robbie B. Mailliard, Adriana T. Larregina, Louis D. Falo, William Gooding, Walter J. Storkus, Hideho Okada, Robert L. Hendricks, Pawel Kalinski
Journal: Cancer Research (2007)

In contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8+ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8+ T cells that kill antigen-carrying dendritic cells, IFNgamma-producing memory CD8+ T cells act as "helper" cells, supporting the ability of dendritic cells to produce interleukin-12 (IL-12) p70. Promoting the interaction of tumor antigen-carrying dendritic cells with memory-type "heterologous" (tumor-irrelevant) CD8+ T cells strongly enhances the IL-12p70-dependent immunogenic and therapeutic effects of vaccination in the animals bearing established tumors. Our data show that the suppressive and helper functions of CD8+ T cells are differentially expressed at different phases of CD8+ T-cell responses. Selective performance of helper functions by memory (in contrast to effector) CD8+ T cells helps to explain the phenomenon of immune memory and facilitates the design of effective therapeutic vaccines against cancer and chronic infections.
Neurocytomas: Long-term experience of a single institution
Authors: A. Hallock, B. Hamilton, L. C. Ang, K. Y. Tay, J. F. Meygesi, B. J. Fisher, C. J. Watling, D. R. Macdonald, G. S. Bauman
Journal: Neuro-Oncology (2011)

There is a lack of studies reporting on outcomes of control and treatment toxicities for neurocytomas.A 25-year retrospective review of a tertiary center's experience with neurocytomas was completed to report on these outcomes.All cerebral neurocytoma cases (19 patients; median age, 31 years; range, 18 -62 years; 18 intraventricular and 1 extraventricular) treated between 1984 and 2009 were analyzed, including central pathology and radiology reviews.Median follow-up was 104.5 months (range, 0.75 -261.7 months).Primary treatment was surgery alone (n 5 18 patients), followed by surgery and adjuvant radiotherapy (n 5 1).The crude local control rate after surgery was 68% for all cases (cerebral neurocytomas) and 74% for central neurocytomas.Salvage therapies included further surgery (n 5 4), radiation (n 5 3), and chemotherapy (n 5 1).Ten-year Kaplan-Meier overall and relapse-free survival rates were 82% and 62% and 81% and 57%, respectively, for all cases and for central neurocytomas only.The median overall survival and relapse-free survival were 104.5 and 79.3 months, respectively, for all cases and for central neurocytomas.Ten patients had grade 3/4 toxicity, and 1 patient had a grade 5 perioperative hemorrhage that resulted in death 23 days after surgery.Late grade 3/4 toxicities occurred in 9 patients.Three patients had permanent grade 2 motor or cognitive deficits.We provide the first report outlining toxicities and survival outcomes in a series of 19 patients.Our experience suggests that initial surgery provides durable local control rates in two-thirds of patients, with low risk for significant permanent deficits.Salvage therapy with surgery and/or radiation provides durable local control in tumors that recur after surgery.
Monocyte- and Cytokine-Induced Downregulation of Angiotensin-Converting Enzyme in Cultured Human and Porcine Endothelial Cells
Authors: Andreas Papapetropoulos, Alexander Antonov, Renu Virmani, Frank D. Kolodgie, David H. Munn, Nandor Marczin, James W. Ryan, Ross G. Gerrity, John D. Catravas
Journal: Circulation Research (1996)

We investigated the effects of monocytes on endothelial cell (EC) ectoenzyme activity. Coculture of human aortic ECs with human monocytes (2×10 5 monocytes per 2-cm 2 well) led to a decrease in EC angiotensin-converting enzyme (ACE) activity (64.5±3.5% of control) but not aminopeptidase N, aminopeptidase P, and 5′-nucleotidase activities. Similar results were obtained using human umbilical vein EC–human monocyte and porcine aortic EC–porcine monocyte cocultures. The decrease in ACE activity was monocyte concentration and coculture time dependent, reaching a maximum of 65% decrease in activity at 120 hours. Monocyte-mediated reduction in ACE activity did not require cell to cell contact, since exposure of ECs to conditioned medium from cocultures (CCCM) or from monocyte cultures (MCM) produced a decrease in ACE activity similar to that observed in EC-monocyte cocultures. Exogenously added tumor necrosis factor (TNF)-α and interleukin (IL)-1α, two known secretory products of monocytes, simulated the effects of monocytes on ACE activity. Western blot analysis revealed a decrease in the amount of ACE protein in TNF-α–treated and CCCM-treated ECs compared with control ECs. Both TNF-α and IL-1α were present in CCCM and MCM but not EC-conditioned medium. Incubation of the cocultures with a mixture of neutralizing antibodies against TNF-α and IL-1 totally abolished the monocyte-induced decrease in ACE activity. In conclusion, monocytes decrease ACE activity in cultured ECs through the release of cytokines such as TNF-α and IL-1.
Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias
Authors: David S. Park, Marina Cerrone, Gregory Morley, Carolina Vasquez, Steven Fowler, Nian Liu, Scott A. Bernstein, Fang-Yu Liu, Jie Zhang, Christopher S. Rogers, Silvia G. Priori, Larry A. Chinitz, Glenn I. Fishman
Journal: Journal of Clinical Investigation (2014)

SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.
Tuberculosis killed 1.5 million people in 2014
Authors: Anne Gulland
Journal: BMJ (2015)

Around 9.6 million people around the world contracted tuberculosis (TB) in 2014, the World Health Organization’s annual update on the disease has estimated.1

This was an increase on the 2013 figure, when nine million people were estimated to be infected, although WHO said that the increase was due to improved national data rather than to any increase in the spread of TB.

The disease is estimated to have affected 5.4 million men, 3.2 million women, and one million children in …
Symptom Fluctuation in Eating Disorders: Correlates of Diagnostic Crossover
Authors: Federica Tozzi, Laura M. Thornton, Kelly L. Klump, Manfred M. Fichter, Katherine A. Halmi, Allan S. Kaplan, Michael Strober, D. Blake Woodside, Scott Crow, James Mitchell, Alessandro Rotondo, Mauro Mauri, Giovanni Cassano, Pamela Keel, Katherine H. Plotnicov, Christine Pollice, Lisa R. Lilenfeld, Wade H. Berrettini, Cynthia M. Bulik, Walter H. Kaye
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The course of anorexia nervosa often includes the emergence of bulimic symptoms and a crossover to the full syndrome of bulimia nervosa. However, clinicians’ ability to predict who will develop bulimia nervosa is limited. The converse phenomenon, crossover from bulimia nervosa to anorexia nervosa, has not been investigated as thoroughly. The authors identified factors that are associated with crossover from anorexia nervosa to bulimia nervosa and from bulimia nervosa to anorexia nervosa. METHOD: All participants were from the International Price Foundation Genetic Study. Two groups were studied. The first comprised 88 individuals with an initial diagnosis of anorexia nervosa, of whom 32 developed bulimia nervosa. The second included 350 individuals with bulimia nervosa, of whom 93 developed anorexia nervosa. Several variables, including DSM-IV axis I and II disorders and personality traits, were evaluated as potential predictors of crossover. RESULTS: For the majority of affected individuals, crossover occurred by the fifth year of illness. A low level of self-directedness was associated with crossover in both directions. Other factors differed by diagnosis: high parental criticism was associated with crossover from anorexia nervosa to bulimia nervosa, whereas alcohol abuse/dependence and a low level of novelty seeking were associated with crossover from bulimia nervosa to anorexia nervosa. CONCLUSIONS: Low self-directedness may be associated with diagnostic instability in general, whereas other specific factors are related to the direction of diagnostic crossover. These results indicate that personality and family characteristics may influence the course of eating disorders and may be informative for planning interventions.
Genetic variability: The key problem in the prevention and therapy of RNA‐based virus infections
Authors: Magdalena Figlerowicz, Magdalena Alejska, Anna Kurzyńska‐Kokorniak, Marek Figlerowicz
Journal: Medicinal Research Reviews (2003)

Abstract Despite extraordinary progress that has recently been made in biomedical sciences, viral infectious diseases still remain one of the most serious world health problems. Among the different types of viruses, those using RNA as their genetic material (RNA viruses and retroviruses) are especially dangerous. At present there is no medicine allowing an effective treatment of RNA‐based virus infections. Many RNA viruses and retroviruses need only a few weeks to escape immune response or to produce drug‐resistant mutants. This seems to be the obvious consequence of the unusual genetic variability of RNA‐based viruses. An individual virus does not form a homogenous population but rather a set of similar but not identical variants. In consequence, RNA‐based viruses can easily adapt to environmental changes, also those resulting from immune system response or therapy. The modifications identified within viral genes can be divided into two groups: point mutations and complex genome rearrangements. The former arises mainly during error‐prone replication, whereas RNA recombination and generic reassortment are responsible for the latter. This article shortly describes major strategies used to control virus infections. Then, it presents the various mechanisms generating the genetic diversity of RNA‐based viruses, which are most probably the main cause of clinical problems. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 4, 488–518, 2003
Mitral Valve Disease in Patients with Marfan Syndrome Undergoing Aortic Root Replacement
Authors: Meghana R. Kunkala, Hartzell V. Schaff, Zhuo Li, Irina Volguina, Harry C. Dietz, Scott A. LeMaire, Joseph S. Coselli, Heidi Connolly
Journal: Circulation (2013)

Background— Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement. Methods and Results— We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade &gt;2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve–sparing procedures; both groups had similar prevalences of MR grade &gt;2 ( P =0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade &gt;2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31±10 months). Echocardiography performed 21±13 months postoperatively revealed MR &gt;2 in only 3 patients (2%). One early death and 2 late deaths occurred. Conclusions— Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤2 would benefit from prophylactic MV intervention.
Zidovudine in Patients with Human Immunodeficiency Virus (HIV) Infection and Kaposi Sarcoma
Authors: H. Clifford Lane
Journal: Annals of Internal Medicine (1989)

Study Objective: To evaluate the toxicity, effects on immune function, antitumor effects, antiretroviral effects, and pharmacokinetics of zidovudine therapy in patients with early human immunodeficiency virus (HIV) infection and Kaposi sarcoma. Design: Randomized, double-blind, placebo-controlled trial. Setting: National Institutes of Health, a referral-based research institution (single site). Patients: Physician-referred volunteer patients with HIV infection, Kaposi sarcoma, CD4+ lymphocyte counts greater than 0.2 X 109/L, and no systemic symptoms or history of opportunistic infection. Of 41 patients enrolled, 4 had not met all entry criteria and were therefore not evaluable. Interventions: Patients were randomized to one of four treatment groups for an initial 12-week treatment period: oral placebo (9 patients); zidovudine, 250 mg orally every 4 hours (9 patients); zidovudine, 0.5 mg/kg body weight intravenously every 4 hours (9 patients); and zidovudine, 2.5 mg/kg intravenously every 4 hours (10 patients). After at least 12 weeks of therapy at their assigned dose, patients were treated with oral zidovudine, generally 250 mg every 4 hours, with a mean 42-week follow-up. Measurements and Main Results: Anemia and granulocytopenia were the major toxicities. Significant increases in platelet counts and declines in serum HIV antigen and IgG and IgM levels occurred in treated patients. Treated patients were more likely than those on placebo to clear HIV from the cerebrospinal fluid. There were no differences in tumor progression or CD4+ or CD8+ lymphocyte counts among the groups. Conclusions: Zidovudine was well tolerated and had antiretroviral activity in patients with early HIV infection and Kaposi sarcoma but it had no significant effect on the extent of Kaposi sarcoma or on immune function.