tbuckley/cabot-search huggingface dataset:
Non-invasive prenatal diagnosis of aneuploidies: new technologies and clinical applications
Authors: Elisavet A Papageorgiou, Philippos C Patsalis
Journal: Genome Medicine (2012)

Non-invasive prenatal diagnosis (NIPD) has substantial medical importance as it targets the development of safer and more effective methods to avoid the risk of fetal loss associated with currently used invasive methods. Several approaches have been demonstrated as being proof-of concept for NIPD of chromosomal aneuploidies. These approaches include cell-based and cell-free detection methods, involving the investigation of fetal cells in the maternal circulation, formaldehyde treatment of maternal plasma, DNA methylation studies using sodium bisulfite or restriction enzymes, protein-based studies, identification of fetal-specific mRNAs and digital polymerase chain reaction (PCR) approaches, and recently next-generation sequencing and methylated DNA immunoprecipitation real-time quantitative PCR-based approaches. Although all these NIPD methods have both advantages and limitations, some are moving closer to clinical implementation. Biotechnology companies dedicated to the development of NIPD tests such as the sequencing- or methylation-based approaches are finalizing large clinical trials. It is expected that these new technologies will facilitate safer, more sensitive and accurate prenatal diagnostic tests in the near future. In this review, we highlight the most recent advances in methods for NIPD of aneuploidies, and we discuss their future implications in clinical practice.
Catheter-Associated Urinary Tract Infection and the Medicare Rule Changes
Authors: Sanjay Saint
Journal: Annals of Internal Medicine (2009)

Catheter-associated urinary tract infection, a common and potentially preventable complication of hospitalization, is 1 of the hospital-acquired complications chosen by the Centers for Medicare & Medicaid Services (CMS) for which hospitals no longer receive additional payment. To help readers understand the potential consequences of the recent CMS rule changes, the authors examine the preventability of catheter-associated infection, review the CMS rule changes regarding catheter-associated urinary tract infection, offer an assessment of the possible consequences of these changes, and provide guidance for hospital-based administrators and clinicians. Although the CMS rule changes related to catheter-associated urinary tract infection are controversial, they may do more good than harm, because hospitals are likely to redouble their efforts to prevent catheter-associated urinary tract infection, which may minimize unnecessary placement of indwelling catheters and facilitate prompt removal. However, even if forcing hospitals to increase efforts to prevent complications stemming from hospital-acquired infection is commendable, these efforts will have opportunity costs and may have unintended consequences. Therefore, how hospitals and physicians respond to the CMS rule changes must be monitored closely.
Cell Proliferation Kinetics and Multistage Cancer Risk Models
Authors: K. T. Bogen
Journal: JNCI Journal of the National Cancer Institute (1989)

Cell-kinetic multistage (CKM) cancer-risk models account for clonal proliferation of postulated intermediate (initiated, premalignant) cell populations during tumorigenesis. To date, almost all CKM models considered have assumed that intermediate, premalignant cells may proliferate exponentially over time in vivo. This “exponential growth” assumption, however, may not always be as biologically plausible as the alternative assumption that cells tend to grow geometrically in time. The general CKM model and applications of it that presume exponential cell growth are reviewed here. Geometric CKM models are then considered, previous erroneous analyses of these models are reviewed, and a corrected mathematical treatment is provided. It is pointed out that the presumption of exponential instead of geometric proliferation kinetics may lead to underestimates of small increments in CKM-predicted cancer risk above background if the geometric assumption is true. An evaluation of pertinent biological evidence is provided, which indicates that precancerous cells may typically proliferate geometrically. Consequently, if CKM models are used for environmental risk assessment, it may be prudent for one to presume geometric cell growth unless specific data support an alternative assumption.
Mitochondrial OPA1, apoptosis, and heart failure
Authors: Le Chen, Qizhi Gong, James P. Stice, Anne A. Knowlton
Journal: Cardiovascular Research (2009)

Mitochondrial fusion and fission are essential processes for preservation of normal mitochondrial function. We hypothesized that fusion proteins would be decreased in heart failure (HF), as the mitochondria in HF have been reported to be small and dysfunctional. Expression of optic atrophy 1 (OPA1), a mitochondrial fusion protein, was decreased in both human and rat HF, as observed by western blotting. OPA1 is important for maintaining normal cristae structure and function, for preserving the inner membrane structure and for protecting cells from apoptosis. Confocal and electron microscopy studies demonstrated that the mitochondria in the failing hearts were small and fragmented, consistent with decreased fusion. OPA1 mRNA levels did not differ between failing and normal hearts, suggesting post-transcriptional control. Simulated ischaemia in the cardiac myogenic cell line H9c2 cells reduced OPA protein levels. Reduction of OPA1 expression with shRNA resulted in increased apoptosis and fragmentation of the mitochondria. Overexpression of OPA1 increased mitochondrial tubularity, but did not protect against simulated ischaemia-induced apoptosis. Cytochrome c release from the mitochondria was increased both with reduction in OPA1 and with overexpression of OPA1. This is the first report, to our knowledge, of changes in mitochondrial fusion/fission proteins in cardiovascular disease. These changes have implications for mitochondrial function and apoptosis, contributing to the cell loss which is part of the downward progression of the failing heart.
Anti-epiligrin cicatricial pemphigoid with IgG autoantibodies to the β and γ subunits of laminin 5
Authors: Wataru Fujimoto, Yôichiro Toi, Fusako Okazaki, Zelmira Lazarova, Kim B. Yancey, Jirô Arata
Journal: Journal of the American Academy of Dermatology (1999)
MDM2 Antagonist Nutlin-3 Displays Antiproliferative and Proapoptotic Activity in Mantle Cell Lymphoma
Authors: Yoko Tabe, Denise Sebasigari, Linhua Jin, Martina Rudelius, Theresa Davies-Hill, Kazunori Miyake, Takashi Miida, Stefania Pittaluga, Mark Raffeld
Journal: Clinical Cancer Research (2009)

Mantle cell lymphoma (MCL) has one of the poorest prognoses of the non-Hodgkin's lymphomas, and novel therapeutic approaches are needed. We wished to determine whether Nutlin-3, a novel small-molecule murine double minute 2 (MDM2) antagonist that efficiently activates TP53, might be effective in inducing cell death in MCL.MCL cell lines with known TP53 status were treated with Nutlin-3, and biological and biochemical consequences were studied. Synergies with the prototypic genotoxic agent doxorubicin and the novel proteasome inhibitor bortezomib were assessed.Nutlin-3 resulted in a reduction in cell proliferation/viability (IC50 < 10 micromol/L), an increase in the apoptotic fraction, and cell cycle arrest in wild-type (wt) TP53 Z-138 and Granta 519 cells. These effects were accompanied by TP53 accumulation and induction of TP53-dependent proteins p21, MDM2, Puma, and Noxa. Cell cycle arrest was characterized by suppression of S phase and an increase in the G0-G1 and G2-M fractions and accompanied by suppression of total and phosphorylated retinoblastoma protein and a decrease in G2-M-associated proteins cyclin B and CDC2. The combination of Nutlin-3 with doxorubicin or bortezomib was synergistic in wt-TP53 MCL cells. Nutlin-3 also induced cell cycle arrest and reduced cell viability in the mutant TP53 MINO cells but at a significantly higher IC50 (22.5 micromol/L). These effects were associated with induction of the TP53 homologue p73, slight increases in p21 and Noxa, and caspase activation. Nutlin-3 and bortezomib synergistically inhibited cell growth of MINO.These findings suggest that the MDM2 antagonist Nutlin-3 may be an effective agent in the treatment of MCL with or without wt-TP53.
Homocysteine and Cardiovascular Disease
Authors: H. Refsum, P. M. Ueland, O. Nygård, S. E. Vollset
Journal: Annual Review of Medicine (1998)

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.
Long-Term Cognitive Impairment after Critical Illness
Authors: P.P. Pandharipande, T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson, B.T. Pun, N.E. Brummel, C.G. Hughes, E.E. Vasilevskis, A.K. Shintani, K.G. Moons, S.K. Geevarghese, A. Canonico, R.O. Hopkins, G.R. Bernard, R.S. Dittus, E.W. Ely
Journal: New England Journal of Medicine (2013)

Survivors of critical illness often have a prolonged and disabling form of cognitive impairment that remains inadequately characterized.We enrolled adults with respiratory failure or shock in the medical or surgical intensive care unit (ICU), evaluated them for in-hospital delirium, and assessed global cognition and executive function 3 and 12 months after discharge with the use of the Repeatable Battery for the Assessment of Neuropsychological Status (population age-adjusted mean [±SD] score, 100±15, with lower values indicating worse global cognition) and the Trail Making Test, Part B (population age-, sex-, and education-adjusted mean score, 50±10, with lower scores indicating worse executive function). Associations of the duration of delirium and the use of sedative or analgesic agents with the outcomes were assessed with the use of linear regression, with adjustment for potential confounders.Of the 821 patients enrolled, 6% had cognitive impairment at baseline, and delirium developed in 74% during the hospital stay. At 3 months, 40% of the patients had global cognition scores that were 1.5 SD below the population means (similar to scores for patients with moderate traumatic brain injury), and 26% had scores 2 SD below the population means (similar to scores for patients with mild Alzheimer's disease). Deficits occurred in both older and younger patients and persisted, with 34% and 24% of all patients with assessments at 12 months that were similar to scores for patients with moderate traumatic brain injury and scores for patients with mild Alzheimer's disease, respectively. A longer duration of delirium was independently associated with worse global cognition at 3 and 12 months (P=0.001 and P=0.04, respectively) and worse executive function at 3 and 12 months (P=0.004 and P=0.007, respectively). Use of sedative or analgesic medications was not consistently associated with cognitive impairment at 3 and 12 months.Patients in medical and surgical ICUs are at high risk for long-term cognitive impairment. A longer duration of delirium in the hospital was associated with worse global cognition and executive function scores at 3 and 12 months. (Funded by the National Institutes of Health and others; BRAIN-ICU ClinicalTrials.gov number, NCT00392795.).
Comparison of Immunofixation, Serum Free Light Chain, and Immunophenotyping for Response Evaluation and Prognostication in Multiple Myeloma
Authors: Bruno Paiva, Joaquin Martinez-Lopez, Maria-Belen Vidriales, Maria-Victoria Mateos, Maria-Angeles Montalban, Elena Fernandez-Redondo, Lourdes Alonso, Albert Oriol, Ana-Isabel Teruel, Raquel de Paz, José-Garcia Laraña, Enrique Bengoechea, Alejandro Martin, Joaquin Diaz Mediavilla, Luis Palomera, Felipe de Arriba, Joan Bladé, Alberto Orfao, Juan-Jose Lahuerta, Jesus F. San Miguel
Journal: Journal of Clinical Oncology (2011)

To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple myeloma (MM) treated with novel agents. Patients and Methods From a total of 260 elderly patients newly diagnosed with MM included in the GEM05&gt;65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study. Results Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction. Conclusion Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
Trypanosoma cruzi: the immunological induction of macrophage plasminogen activator requires thymus-derived lymphocytes.
Authors: N Nogueira, S Gordon, Z Cohn
Journal: The Journal of Experimental Medicine (1977)

In this article we describe methods in which unstimulated mouse peritoneal macrophages were induced to secrete high livels of plasminogen activator under in vitro conditions. The exposure of sensitized peritoneal or spleen cell populations from Trypanosoma cruzi-infected animals to either viable or heat-killed trypanosomes lead to the release of an inducing factor(s). Maximal levels of plasminogen activator secretion are achieved by the incubation of such factors (s) with unstimulated macrophages for 48 h. A significant increase in enzyme secretion was already observed after a 24 h incubation. The production of the inducing factor(s) by sensitized cells was immunologically specific and unrelated antigens did not stimulate the production of the factor(s) by sensitized peritoneal or spleen cell populations. The inducing factor(s) was produced by nylon-wool-fractionated spleen and peritoneal cells which had been depleted of marcrophages. Pretreatment of sensitized spleen cells with anti-theta serum and C abolished the production of the activating factor(s). The active supernatant fluids were able to induce secretion of macrophage plasminogen activator across H-2 barriers. Attempts to induce trypanocidal activity in unstimulated macrophages have not been successful.
Metabolic changes in schizophrenia and human brain evolution
Authors: Philipp Khaitovich, Helen E Lockstone, Matthew T Wayland, Tsz M Tsang, Samantha D Jayatilaka, Arfu J Guo, Jie Zhou, Mehmet Somel, Laura W Harris, Elaine Holmes, Svante Pääbo, Sabine Bahn
Journal: Genome biology (2008)

Abstract Background Despite decades of research, the molecular changes responsible for the evolution of human cognitive abilities remain unknown. Comparative evolutionary studies provide detailed information about DNA sequence and mRNA expression differences between humans and other primates but, in the absence of other information, it has proved very difficult to identify molecular pathways relevant to human cognition. Results Here, we compare changes in gene expression and metabolite concentrations in the human brain and compare them to the changes seen in a disorder known to affect human cognitive abilities, schizophrenia. We find that both genes and metabolites relating to energy metabolism and energy-expensive brain functions are altered in schizophrenia and, at the same time, appear to have changed rapidly during recent human evolution, probably as a result of positive selection. Conclusion Our findings, along with several previous studies, suggest that the evolution of human cognitive abilities was accompanied by adaptive changes in brain metabolism, potentially pushing the human brain to the limit of its metabolic capabilities.
Decreased neointimal formation in Mac-1–/– mice reveals a role for inflammation in vascular repair after angioplasty
Authors: Daniel I. Simon, Zhiping Chen, Philip Seifert, Elazer R. Edelman, Christie M. Ballantyne, Campbell Rogers
Journal: Journal of Clinical Investigation (2000)

Inflammation plays an essential role in the initiation and progression of atherosclerosis, but its role in vascular repair after mechanical arterial injury (i.e., percutaneous transluminal coronary angioplasty, PTCA) is unknown. In animal models of vascular injury, leukocytes are recruited as a precursor to intimal thickening. Furthermore, markers of leukocyte activation — in particular, increased expression of the β2-integrin Mac-1 (αMβ2, or CD11b/CD18), which is responsible for firm leukocyte adhesion to platelets and fibrinogen on denuded vessels — predict restenosis after PTCA. To determine whether Mac-1–mediated leukocyte recruitment is causally related to neointimal formation, we subjected mice lacking Mac-1 to a novel form of mechanical carotid artery dilation and complete endothelial denudation. We now report that the selective absence of Mac-1 impairs transplatelet leukocyte migration into the vessel wall, reducing leukocyte accumulation over time. Diminished medial leukocyte accumulation was accompanied by markedly reduced neointimal thickening after vascular injury. These data establish a role for inflammation in neointimal thickening and suggest that leukocyte recruitment to mechanically injured arteries may prevent restenosis.
The plain Radiograph in Ophthalmology: A Wasteful and Potentially Dangerous Anachronism
Authors: I F Moseley
Journal: Journal of the Royal Society of Medicine (1991)

The indications for 822 consecutive referrals for skull radiography were prospectively studied in a large eye hospital over a one year period. In 85.9% of patients the results were normal, and in 89% of the remainder they had no positive effects on management; all patients in whom a 'beneficial' effect could be identified would have been more appropriately investigated by other means. Fourteen of 25 patients whose skull radiographs were normal were shown by computed tomography or magnetic resonance imaging to have orbital or intracranial lesions. Views of the optic canals, orbits or paranasal sinuses were also requested in 336 patients. With appropriate use of alternative imaging methods, no patient's treatment would have been adversely affected if none of the skull radiographs had been obtained.
Autonomic neuropathy in systemic lupus erythematosus: cardiovascular autonomic function assessment.
Authors: F Liote, C K Osterland
Journal: Annals of the Rheumatic Diseases (1994)

AIM--To assess the prevalence and the nature of autonomic neuropathy (AN) in 17 patients with inactive or mild active systemic lupus erythematosus (SLE). METHODS--Patients were tested using questionnaires related to possible AN symptoms, and four non invasive cardiovascular autonomic function tests at rest, during lying to standing, and sustained handgrip. Eleven age matched normal subjects were also enrolled as a control group. RESULTS--At least one abnormal cardiovascular autonomic function test was observed in 15 of the 17 patients. The two groups did not differ in deep-breathing (parasympathetic, PS) and handgrip tests (sympathetic, S) although responses in patients with SLE tended towards abnormal values. Statistical differences were found in standing-heart rate ratio (R-R ratio) (PS) with a lower ratio in the group with SLE (p &lt; 0.01) and in standing blood pressure with a higher decrease in systolic blood pressure (p &lt; 0.05) in patients with SLE. No correlation was found between AN, age, disease duration and presence of Raynaud9s phenomenon. CONCLUSION--In inactive or mild active SLE, AN could represent residual abnormalities of autonomic nervous system involvement and/or could be related to glucocorticoids.
Smoking and the Kidney
Authors: Stephan R. Orth
Journal: Journal of the American Society of Nephrology (2002)

Nephrologists "rediscovered" smoking as a major renal risk factor in 1997 ([1][1]), although investigators in the 19th and 20th centuries had noted an association between smoking and renal damage ([2][2]). In the past few years the knowledge about the renal risks of smoking has expanded rapidly
Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor
Authors: Shashank Gupta, Sandeep Tyagi, Deepak V. Almeida, Mariama C. Maiga, Nicole C. Ammerman, William R. Bishai
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy.Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/pharmacodynamic relationships of verapamil and rifampin coadministration in mice.Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice.We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone.These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.