tbuckley/cabot-search huggingface dataset:
The role of the cytoskeleton in heart failure
Authors: S Hein
Journal: Cardiovascular Research (2000)

The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of alpha- and beta-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membrane-associated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, alpha-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material. (2) Further accumulation of microtubules and desmin to compensate for the increasing loss of myofilaments and titin represents the late clinical and irreversible state. We suggest, based on a structural basis for heart failure, an integrative view which closes the gap between changes within cardiac myocytes and the involvement of the extracellular matrix, including the development of fibrosis. These factors contribute significantly to structural ventricular remodeling and dilatation finally resulting in reduced cardiac function.
Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.
Authors: J M Lindstrom, A G Engel, M E Seybold, V A Lennon, E H Lambert
Journal: The Journal of Experimental Medicine (1976)

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.
Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer’s disease
Authors: Shuk Wai Ho, Yuk Tung Chanel Tsui, Ting Ting Wong, Stanley Kwok-Kuen Cheung, William B Goggins, Lau Ming Yi, Kwok Kin Cheng, Larry Baum
Journal: Translational Neurodegeneration (2013)

Alzheimer's disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation.
Sodium, Blood Pressure, and Cardiovascular Disease
Authors: Paul K. Whelton
Journal: Circulation (2014)

T he relationship between sodium (Na) intake and human health indicators has been investigated in observational studies and randomized, controlled trials.The most extensive body of information details the relationship between Na and blood pressure (BP).High BP was identified as the leading risk factor, among 67 studied, for worldwide mortality and disability adjusted life years. 14][5] The decrements in BP were greater in those with higher starting levels of BP, more successful intervention, older age, and African-American ethnicity.In the 2 meta-analyses with greatest relevance for clinical practice and public health, Na reduction was associated with a small but expected physiological increase in elements of the renin-angiotensin-aldosterone system, 3,4 little or no effect on total cholesterol 3,4 or catecholamine levels, 3 and changes in urinary protein consistent with a beneficial effect on renal function.
A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference
Authors: M. Piram, J. Frenkel, M. Gattorno, S. Ozen, H. J. Lachmann, R. Goldbach-Mansky, V. Hentgen, B. Neven, K. S. Stojanovic, A. Simon, J. Kuemmerle-Deschner, H. Hoffman, S. Stojanov, A. Duquesne, P. Pillet, A. Martini, J. Pouchot, I. Kone-Paut
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background</h3> The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). <h3>Methods</h3> The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. <h3>Results</h3> 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0–13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. <h3>Conclusion</h3> Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow.
Plasma MicroRNA Are Disease Response Biomarkers in Classical Hodgkin Lymphoma
Authors: Kimberley Jones, Jamie P. Nourse, Colm Keane, Atul Bhatnagar, Maher K. Gandhi
Journal: Clinical Cancer Research (2013)

Although microRNAs (miRNA) show potential as diagnostic biomarkers in cancer, their role as circulating cell-free disease response biomarkers remains unknown. Candidate circulating miRNA biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin-Reed-Sternberg (HRS) cells and/or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, embedded within a benign microenvironment, the composition of which is distinct from that seen in healthy lymph nodes.Microarray profiling of more than 1,000 human miRNAs in 14 cHL primary tissues and eight healthy lymph nodes revealed a number of new disease node-associated miRNAs, including miR-494 and miR-1973. Using quantitative real-time PCR (qRT-PCR), we tested the utility of these, as well as previously identified disease node-associated plasma miRNAs (including miR-21 and miR-155), as disease response biomarkers in a prospective cohort of 42 patients with cHL. Blood samples were taken in conjunction with radiologic imaging at fixed time points before, during, and after therapy. Absolute quantification was used so as to facilitate implementation in diagnostic laboratories.Levels of miR-494, miR-1973, and miR-21 were higher in patients than control (n = 20) plasma (P = 0.004, P = 0.007, and P < 0.0001, respectively). MiR-494 and miR-21 associated with Hasenclever scores ≥3. Strikingly, all three miRNAs returned to normal at remission (P = 0.0006, P = 0.0002, and P < 0.0001 respectively). However, only miR-494 and miR-1973 reflected interim therapy response with reduction being more pronounced in patients achieving complete versus partial responses (P = 0.043 and P = 0.0012, respectively).Our results demonstrate that in patients with cHL, circulating cell-free miRNAs can reflect disease response once therapy has commenced.
A Step Toward Genotype-Based Therapeutic Regimens for Breast Cancer in Patients With BRCA2 Mutations?
Authors: P. J. Biggs, A. Bradley
Journal: JNCI Journal of the National Cancer Institute (1998)

The positional cloning of a familial tumor suppressor gene is a monumental task often involving the coordinated efforts of international consortia of many laboratories. The euphoria that accompanies the successful cloning of a cancer-causing gene signals the initiation of many new avenues of study that attempt to define the activity of that gene’s product. These goals are laudatory, because by defining such a function and understanding how it is subverted by mutations, the hope is that eventually this information can be used to develop therapeutic approaches aimed at patients and their family members who participated selflessly in the genetic studies that ultimately led to the identification of the gene. The biologic functions of gene products are hugely diverse, and our knowledge base of gene function is currently so poor that the experimental pathways that lead to the elucidation of a gene’s function are not necessarily easy to discern. Usually, many years elapse between the cloning of a familial tumor suppressor gene and the identification of its function. Moreover, although valuable information will be garnered about a gene’s function, translating this knowledge into effective therapeutic regimens, based on the knowledge of an individual’s genetic lesion, is extremely difficult. However, an article appearing in this issue of the Journal (1), as well as two other articles (2,3), suggests that genotype-based therapeutics for familial breast cancer caused by lesions in the BRCA2 gene may be possible. All of these studies show that cell lines lacking functional BRCA2 are hypersensitive to agents that
The Psychoses of Epilepsy
Authors: B K Toone
Journal: Journal of the Royal Society of Medicine (1991)

People who have epilepsy seem particularly liable to certain major psychiatric disorders: a chronic interictal psychosis that closely resembles schizophrenia; and episodic psychotic states, some of which may arise in close temporal relation with seizure activity. These disorders are conventionally referred to as the psychoses of epilepsy although some of the episodic forms would be more accurately described as acute confusional states. These conditions have for long puzzled and intrigued psychiatrists and neurologists, but in recent years this interest has quickened especially among biologically minded psychiatrists in search of a neurological model for schizophrenia. In the psychoses of epilepsy and in schizophrenia converging lines of enquiry, in neuroimaging and in neuropathology in particular, have implicated the mesial temporal structures, the more so in the dominant hemisphere, and comparable abnormalities have been reported.1 This review will seek to identify areas of progress, areas of difficulty, and persisting dilemmas.

The precise nature of this relation has taxed clinical observers since before the turn of the century. Over the past four decades a consensus has begun to take shape—namely, that certain forms of epilepsy may act as risk factors for the subsequent development of a chronic interictal psychosis, a syndrome sometimes referred to as the schizophrenia-like psychoses of epilepsy (SLPE). This psychosis does resemble schizophrenia in its phenomenological manifestations,2 3 pursues a similar course, is as responsive to antipsychotic medication, and is largely uninfluenced by concurrent seizure activity. Given these similarities it is reasonable to question whether this comorbidity could not have arisen as a result of a chance association between two relatively common disorders. The answer should lie in community based comparisons of unbiased samples of epileptic and non-epileptic subjects with respect to prevalence of psychosis. Attempts have been made to do this, yielding a prevalence of schizophrenia within an …
Using patient-reported outcome measures to estimate cost-effectiveness of hip replacements in English hospitals
Authors: John Appleby, Emmi Poteliakhoff, Koonal Shah, Nancy Devlin
Journal: Journal of the Royal Society of Medicine (2013)

Objective To estimate the average cost per quality adjusted life year (QALY) gained from hip surgery, and to examine the variation in that between hospitals. Design The transformation of patient-reported outcome measures (EQ-5D data) into QALYs, covering 25,463 NHS patient episodes between April 2009 and August 2010 from hospitals in England, using a model of future health change arising from a hip operation compared to a counterfactual of no operation. Hospital-level costs for hip procedures from the National Reference Costs data-set was used to calculate the hospitals' cost per QALY. Setting English hospitals treating NHS-funded patients undergoing hip replacement. Participants NHS-funded patients undergoing primary hip replacement. Main outcome measure Cost per QALY. Results Assuming some degradation in patients’ health over the lifetime of the hip prosthesis, average health gain arising from a hip operation was 2.77 QALYs. For procedures paid for by the NHS but carried out in the independent sector the average gain was 2.97 QALYs. Average NHS hospital hip procedure costs were estimated to be £5844. The unweighted average cost per QALY for NHS hospitals was £2128. There were significant variations in cost per QALY between hospitals; most of this variation appears to be driven by variations in cost, not QALYs. Conclusions Using the new patient-assessed health-related quality of life data combined with routine hospital-level cost data it is possible to estimate a procedure-based measure of efficiency for hospitals. The fact that variations in cost per QALY are strongly driven by variations in cost suggests that further work is needed to investigate the causes of cost variations per se – especially the quality of routine NHS cost data.
Lung biopsy guidelines--for the obedience of fools and guidance of wise men
Authors: A R Manhire
Journal: Thorax (2003)

Lung biopsy is not without morbidity and occasionally mortality

Percutaneous transthoracic lung biopsy is thought to have been developed by Leyden in 1883 in order to diagnose pneumonia. The technique was extended to the diagnosis of cancer from the 1930s onwards, but at that time there was a significant complication rate, primarily associated with the use of large bore needles. The more widespread use of the technique in the 1960s and 1970s was heralded by the development of high resolution image intensification and improved cytological techniques, which permitted the use of smaller needles and reduced complications. One hundred and twenty years after its inception, percutaneous lung biopsy is now a generally accepted and widely used method of establishing the aetiology of lung masses.

Despite its usefulness, the procedure is not without its morbidity and rarely mortality. It was one of these rare deaths that prompted a search for current standards of good practice. A survey published in 2002 by Richardson et al ,1 in which all known centres performing lung biopsy in the United Kingdom were invited to participate, showed that practice varied greatly across the country. Some centres reported undertaking as few as three biopsies a year and others over 200. There appeared to be …
Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)–deficient mice
Authors: Helena E. Miettinen, Helen Rayburn, Monty Krieger
Journal: Journal of Clinical Investigation (2001)

Mammalian female fertility depends on complex interactions between the ovary and the extraovarian environment (e.g., the hypothalamic-hypophyseal ovarian axis). The role of plasma lipoproteins in fertility was examined using HDL-receptor SR-BI knockout (KO) mice. SR-BI KO females have abnormal HDLs, ovulate dysfunctional oocytes, and are infertile. Fertility was restored when the structure and/or quantity of abnormal HDL was altered by inactivating the apoAI gene or administering the cholesterol-lowering drug probucol. This suggests that abnormal lipoprotein metabolism can cause murine infertility — implying a functional hepatic-ovarian axis — and may contribute to some forms of human female infertility.
Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments Anti-CD40 SGN-40–Induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications
Authors: Yu-Tzu Tai, Xian-Feng Li, Laurence Catley, Rory Coffey, Iris Breitkreutz, Jooeun Bae, Weihua Song, Klaus Podar, Teru Hideshima, Dharminder Chauhan, Robert Schlossman, Paul Richardson, Steven P. Treon, Iqbal S. Grewal, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Cancer Research (2005)

Abstract SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6–induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40–induced cytotoxicity against CD138+CD40+ MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40–induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G0 cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40–induced MM cell lysis, associated with an increased number of CD56+CD3− natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell–mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56+CD3− NK cells, facilitating IL-2–mediated activation of NK cells. In addition, lenalidomide induced the CD56dim NK subset, which are more potent mediators of ADCC against target MM cells than the CD56bright NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40–mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM. (Cancer Res 2005; 65(24): 11712-20)
Dietary Sodium Intake in Heart Failure
Authors: Divya Gupta, Vasiliki V. Georgiopoulou, Andreas P. Kalogeropoulos, Sandra B. Dunbar, Carolyn M. Reilly, Jeff M. Sands, Gregg C. Fonarow, Mariell Jessup;, Mihai Gheorghiade, Clyde Yancy, Javed Butler
Journal: Circulation (2012)