tbuckley/cabot-search huggingface dataset:
Congruent Evolution of Genetic and Environmental Robustness in Micro-RNA
Authors: G. J. Szollosi, I. Derenyi
Journal: Molecular Biology and Evolution (2009)

Genetic robustness, the preservation of an optimal phenotype in the face of mutations, is critical to the understanding of evolution as phenotypically expressed genetic variation is the fuel of natural selection. The origin of genetic robustness, whether it evolves directly by natural selection or it is a correlated byproduct of other phenotypic traits, is, however, unresolved. Examining micro-RNA (miRNA) genes of several eukaryotic species, Borenstein and Ruppin (Borenstein E, Ruppin E. 2006. Direct evolution of genetic robustness in microRNA. Proc Natl Acad Sci USA. 103: 6593) showed that the structure of miRNA precursor stem loops exhibits significantly increased mutational robustness in comparison with a sample of random RNA sequences with the same stem-loop structure. The observed robustness was found to be uncorrelated with traditional measures of environmental robustness—implying that miRNA sequences show evidence of the direct evolution of genetic robustness. These findings are surprising as theoretical results indicate that the direct evolution of robustness requires high mutation rates and/or large effective population sizes only found among RNA viruses, not multicellular eukaryotes. We demonstrate that the sampling method used by Borenstein and Ruppin introduced significant bias that lead to an overestimation of robustness. Introducing a novel measure of environmental robustness based on the equilibrium thermodynamic ensemble of secondary structures of the miRNA precursor sequences, we demonstrate that the biophysics of RNA folding induces a high level of correlation between genetic (mutational) and environmental (thermodynamic) robustness, as expected from the theory of plastogenetic congruence introduced by Ancel and Fontana (Ancel LW, Fontana W. 2000. Plasticity, evolvability, and modularity in RNA. J Exp Zool. 288: 242–283). In light of theoretical considerations, we believe that this correlation strongly suggests that genetic robustness observed in miRNA sequences is the byproduct of selection for environmental robustness.
Euthanasia: death, dying and the medical duty
Authors: J. J M Van Delden
Journal: BMJ (1996)

Eds G R Dunstan, P J Lachmann Royal Society of Medicine Press, £45, pp 172 ISBN 185315 278 1

There seem to be three main ways of dealing with the issue of voluntary euthanasia, understood here to mean the deliberate and intentional hastening of death at a patient's request. The first is to reject it, citing the ethical principle of respect for life. This position is also defended by pointing to the risk of crossing the line from voluntary euthanasia to involuntary killing: the “slippery slope” argument. Defenders of this view sometimes claim that euthanasia is not necessary at all. They believe that, for people who request euthanasia, there is a “question behind the question,” which will surely turn out to be something other than a request for dying—if one listens hard …
Genome-Wide Identification of Genes Conferring Resistance to the Anticancer Agents Cisplatin, Oxaliplatin, and Mitomycin C
Authors: H. Irene Wu, James A. Brown, Mary J. Dorie, Laura Lazzeroni, J. Martin Brown
Journal: Cancer Research (2004)

Abstract Cisplatin is a crucial agent in the treatment of many solid tumors, yet many tumors have either acquired or intrinsic resistance to the drug. We have used the homozygous diploid deletion pool of Saccharomyces cerevisiae, containing 4728 strains with individual deletion of all nonessential genes, to systematically identify genes that when deleted confer sensitivity to the anticancer agents cisplatin, oxaliplatin, and mitomycin C. We found that deletions of genes involved in nucleotide excision repair, recombinational repair, postreplication repair including translesional synthesis, and DNA interstrand cross-link repair resulted in sensitivity to all three of the agents, although with some differences between the platinum drugs and mitomycin C in the spectrum of required translesional polymerases. Putative defective repair of oxidative damage (imp2′Δ strain) also resulted in sensitivity to platinum and oxaliplatin, but not to mitomycin C. Surprisingly in light of their different profiles of clinical activity, cisplatin and oxaliplatin have very similar sensitivity profiles. Finally, we identified three novel genes (PSY1–3, “platinum sensitivity”) that, when deleted, demonstrate sensitivity to cisplatin and oxaliplatin, but not to mitomycin C. Our results emphasize the importance of multiple DNA repair pathways responsible for normal cellular resistance to all three of the agents. Also, the similarity of the sensitivity profiles of the platinum agents with that of the known DNA interstrand cross-linking agent mitomycin C, and the importance of the gene PSO2 known to be involved in DNA interstrand cross-link repair strongly suggests that interstrand cross-links are important toxic lesions for cisplatin and oxaliplatin, at least in yeast.
Intracellular Calcium Concentration in the Inositol Trisphosphate Receptor Type 1 Knockout Mouse
Authors: MATSUHIKO HAYASHI, TOSHIAKI MONKAWA, TADASHI YOSHIDA, HIROYUKI SASAMURA, MINEO MATSUMOTO, TAKAFUMI INOUE, KATSUHIKO MIKOSHIBA, TAKAO SARUTA
Journal: Journal of the American Society of Nephrology (1999)

Recently, mice with a disrupted inositol trisphosphate (IP3) receptor type 1 allele were produced by gene targeting. To examine the role of IP3 receptor type I in the regulation of intracellular calcium concentration ([Ca2+]i) of glomerular cells, [Ca2+]i was measured with fura 2-acetoxymethyl-ester in the superfused glomeruli from homozygous and wild-type mice. [Ca2+]i was determined in calcium-free medium before and after the addition of 10(-7) M endothelin-1 (ET-1) and 10(-6) M angiotensin II (AngII). The expression of mRNA of IP3 receptor isoforms and hormone receptors in the glomeruli from these animals also was measured by quantitative reverse transcription-PCR with specific primers for IP3 receptor isoforms (types 1, 2, and 3), AngII receptor type 1, and ET receptors (types A and B). In homozygous mutants, the shorter mRNA of IP3 receptor type 1, which lacks the first exon, is transcribed. Basal [Ca2+]i and the responses to ET-1 and AngII in homozygous mutants (ET-1, 55 +/- 7 nM to 73 +/- 7 nM; AngII, 66 +/- 6 to 91 +/- 8 nM) were significantly lower than those in the wild-type mice (ET-1, 93 +/- 13 nM to 162 +/- 13 nM; AngII, 87 +/- 7 to 147 +/- 9 nM; P < 0.05 for both hormones) without significant changes in mRNA expression of hormone receptors. The results with quantitative reverse transcription-PCR also revealed that mRNA expression of the IP3 receptor gene family was not significantly different between the two groups. The present study clearly shows that IP3 receptor type 1 plays a major role in the regulation of [Ca2+]i in the glomeruli and that lack of an isoform of IP3 receptor in the glomeruli does not induce expression of the other isoforms of the IP3 receptor.
Value of synovial fluid interleukin-1 beta determination in predicting the outcome of psoriatic monoarthritis.
Authors: L Punzi, N Bertazzolo, M Pianon, E Rizzi, P Rossini, P Gambari
Journal: Annals of the Rheumatic Diseases (1996)

To investigate the value of synovial fluid analysis in predicting the outcome of psoriatic monoarthritis.In synovial fluid from knee joints of 18 patients with psoriatic monoarthritis lasting less than six months, white blood cell count, acid phosphatase, lysozyme, and interleukin (IL)-1 beta were determined. ESR and serum C reactive protein were also measured. To define the outcome, the patients were monitored for at least three years and then subdivided into those with polyarthritis and those without.Among the blood and synovial fluid indices considered, synovial fluid IL-1 beta was the only variable which differed between the patients who developed polyarthritis, within three years and those without polyarthritis after this time, at 20.82(SD 8.79) v 4.19(4.73) pg ml-1, P < 0.0001). A correlation was found between synovial fluid IL-1 beta concentrations and the number of affected joints after three years (r = 0.739, P < 0.0001).Determination of synovial fluid IL-1 beta at disease onset may be useful in revealing the outcome of psoriatic monoarthritis since, among the variables considered in our study, this was the only one capable of predicting the evolution of monoarticular psoriatic arthritis to polyarthritis.
Risk of depression in patients with chronic obstructive pulmonary disease and its determinants
Authors: J G van Manen
Journal: Thorax (2002)

Background: Although it has been repeatedly suggested that chronic obstructive pulmonary disease (COPD) is associated with depression, no conclusion has so far been reached. A study was undertaken to investigate whether depression occurs more often in patients with COPD than in controls. The demographic and clinical variables associated with depression were also determined. Methods: Patients with a registered diagnosis of obstructive airway disease in general practice, aged ≥40 years, forced expiratory volume in 1 second (FEV<sub>1</sub>) &lt;80% predicted, FEV<sub>1</sub> reversibility ≤12%, FEV<sub>1</sub>/VC ≤ predicted – 1.64 × SD, and a history of smoking were selected. A random sample of subjects without a registered diagnosis of asthma or COPD aged 40 years or older acted as controls. Depression was assessed using the Centers for Epidemiologic Studies Depression (CES-D) scale. Results: In patients with severe COPD (FEV<sub>1</sub> &lt;50% predicted), the prevalence of depression was 25.0% compared with 17.5% in controls and 19.6% in patients with mild to moderate COPD. When the results were adjusted for demographic variables and comorbidity, the risk for depression was 2.5 times greater for patients with severe COPD than for controls (OR 2.5, 95% CI 1.2 to 5.4). In patients with mild to moderate COPD this increased risk of depression was not seen. Living alone, reversibility of FEV<sub>1</sub> % predicted, respiratory symptoms and physical impairment were significantly associated with the scores on the CES-D scale. Conclusion: Patients with severe COPD are at increased risk of developing depression. The results of this study underscore the importance of reducing symptoms and improving physical functioning in patients with COPD.
How Can We Measure Immunologic Tolerance in Humans?
Authors: Nader Najafian, Monica J. Albin, Kenneth A. Newell
Journal: Journal of the American Society of Nephrology (2006)

Prevention and treatment of allograft rejection in organ transplant recipients relies primarily on non–antigen-specific immunosuppression, with all its associated potential hazards and costs. Currently, the status of the recipient immune response is measured by monitoring pharmacologic drug levels and clinical/pathologic evaluation of graft function. Development of reliable assays that can measure accurately the status of the immune response not only would help clinicians customize the prescription of immunosuppressive drugs in individual patients but also may allow their complete withdrawal in some patients with immunologic tolerance. Furthermore, these assays would facilitate the safe evaluation of novel tolerogenic regimens. Achieving this goal has proved to be very difficult because it requires both a more in-depth understanding of complex mechanisms of tolerance and also identification of transplant patients with acquired tolerance to an allograft that can be studied. This review discusses the current understanding of tolerance mechanisms and outlines the unique and specific challenges in development of tolerance/monitoring assays in the field of transplantation. In addition, several of the most promising candidate assays are discussed in detail.
Respective roles of H-ATPase and H-K-ATPase in ion transport in the kidney.
Authors: L C Garg
Journal: Journal of the American Society of Nephrology (1991)

Two types of proton-translocating ATPases, H-ATPase and H-K-ATPase, are found in the renal tubular cells. H-ATPase is present in both endocytic vesicles and apical membranes in almost all nephron segments. On the other hand, H-K-ATPase is present only in the connecting tubule and collecting duct. There is evidence to suggest that H-ATPase may be involved in H secretion in almost all nephron segments. H-K-ATPase is involved not only in H secretion but also in K absorption in the collecting duct segments. Aldosterone administration and metabolic acidosis stimulate the activity of H-ATPase in all collecting duct segments, whereas hypokalemia has only a limited effect on H-ATPase activity. On the other hand, hypokalemia, as well as metabolic acidosis, stimulates H-K-ATPase activity in the collecting duct segments, whereas aldosterone administration alone plays a minor role in the regulation of this enzyme. The physiological role and regulation of H-ATPase in the proximal tubule has not been established.
Randomized Controlled Trial of a New Dietary Education Program to Prevent Type 2 Diabetes in a High-Risk Group of Japanese Male Workers
Authors: Mariko Watanabe, Kazue Yamaoka, Masako Yokotsuka, Toshiro Tango
Journal: Diabetes Care (2003)

OBJECTIVE—The aim of this study was to assess the effectiveness of a new dietary education (NDE) program in reducing plasma glucose (PG) levels in Japanese male workers at high risk for type 2 diabetes through a randomized controlled trial. RESEARCH DESIGN AND METHODS—We randomly assigned 173 high-risk men (mean age, 55 years) to either the NDE or the control (conventional dietary education) group. Each subject in the NDE group received two individualized interventions especially aimed at reducing total energy intake at dinner by modifying dietary intake. The control group received conventional group counseling. An “overintake/underintake fraction” for total energy intake was used to measure the status of dietary intake. Our hypothesis was that the NDE group would have a 10% decrease in 2-h PG 1 year after the start of the education. Outcome measures were compared with ANCOVA by adjusting for baseline values. RESULTS—The NDE group had a significantly lower total energy intake at dinner and daily than the control group. The adjusted differences in changes from baseline in the absolute value of the “overintake/underintake fraction” were −15.3% (95% CI −24.6 to −6.0%, P = 0.002) for the NDE group and −6.0% (−9.8 to −2.2%, P = 0.002) for the control group. The NDE group had a decreased 2-h PG after 1 year, whereas that value was increased in the control group. The adjusted difference in the percent change of 2-h PG was significant (−15.2%, −22.0 to −8.4%, P &amp;lt; 0.001). CONCLUSIONS—The NDE was shown to reduce glucose levels in high-risk subjects for type 2 diabetes.
Acitretin monotherapy in Darier's disease
Authors: R.J. DOOREN-GREEBE, P.C.M. KERKHOF, R. HAPPLE
Journal: British Journal of Dermatology (1989)

The dose response relationship to acitretin in five patients with Darier's disease was investigated. The patients received in the first 3 months 35 mg daily, and the dose was adjusted according to the clinical response. Four of the five patients showed a marked improvement with up to total clearance, although in two patients isomorphic reactions due to a relative overdose were seen. These isomorphic reactions improved with a reduction of dose. We suggest that treatment with acitretin is initiated at 10–25 mg daily with gradual adjustment of the dose.
REGRESSIVE EST, CHLORPROMAZINE, AND GROUP THERAPY IN TREATMENT OF HOSPITALIZED CHRONIC SCHIZOPHRENICS
Authors: PETER D. KING
Journal: American Journal of Psychiatry (1958)

1. A rating scale was devised for evaluating chronic mental patients. 2. By using this rating scale and certain other criteria, 19 sets of 5 carefully matched chronic schizophrenics were formed. Five groups of 19 patients each were randomly formed to compare the results of REST, REST plus group psychotherapy, chlorpromazine, and chlorpromazine plus group psychotherapy. One group contained matched controls. 3. REST was followed in 6 months by a significant lowering in rating score in comparison to the control group. 4. Weekly group therapy among REST patients restored them to a pre-treatment level. 5. Chlorpromazine resulted in a significant improvement in rating score in comparsion to the matched control group. Weekly group therapy resulted in slightly greater improvement, but it was not statistically significant.
Diseases of the Lung Resulting from Occupational Dusts other than Silica
Authors: K. M. A. Perry
Journal: Thorax (1947)

It is only in recent years that considerable interest has been given to the dusts to which men are exposed at their work, even though silicosis is known to have occurred in prehistoric times.Many dusts are now recognized as dangerous, and in the extreme it may even be doubted whether any dust can be regarded as harmless.It is rational at least to suppose that the lung cannot become a physiological dust trap and yet retain its elasticity.It seems possible that any dust, no matter how innocuous in small concentrations, would in large enough quantity eventually overwhelm the defences of the lung and accumulate in such amounts as to impair function; such a form of lung disease would be the result of causes of a mechanical nature-the physical presence of large amounts of inert foreign material.The term "benign pneumoconiosis " has been given to this type of disease in order to contrast it with diseases resulting from the inhalation of siliceous matter.But besides this group of conditions occupational dust may give rise to inflammatory lesions, allergic responses, and neoplastic changes. INFLAMMATORY CHANGESInflammatory changes may be caused by inorganic metals, such as manganese, beryllium, vanadium, and osmium, giving.rise to a chemical pneumonitis; and by organic matter, such as decaying hay and grain, bagasse, cotton fibre, and similar substances where the aetiology is somewhat obscure, though fungi are frequently blamed. ManganeseManganese occurs in nature as the oxide in the ores pyrolusite, braunite, hausmanite, and manganite, which are found in Russia, India, the Gold Coast of Africa, Brazil, the United States, and Cuba.Manganese appears to be an essential substance in plant and animal nutrition.Its most important alloys are spiegeltisen and ferro-manganese, but silico-manganese and silico-spiegel are used in certain grades of steel.Manganese bronze is used for marine construction and mining machinery where corrosion is serious.
THE EFFECT OF CETADIOL ON DELIRIUM TREMENS, ALCOHOLIC HALLUCINOSIS, AND ALCOHOL WITHDRAWAL
Authors: D. WEXLER, P. H. LEIDERMAN, J. MENDELSON, P. KUBZANSKY, P. SOLOMON
Journal: American Journal of Psychiatry (1958)

Cetadiol does not have a tranquilizing or sedating effect on patients suffering from delirium tremens or alcoholic hallucinosis. It does not shorten the course of delirium tremens. The placebo used in this study is as effective as Cetadiol in relieving symptoms of alcohol withdrawal. [See Source PDF for table 1]
Primary mediastinal tumours
Authors: Y. D. Al-Naaman, M. S. Al-Ani, M. M. Al-Omeri
Journal: Thorax (1974)

<b>Al-Naaman, Y. D., Al-Ani, M. S., and Al-Omeri, M. M. (1974).</b><i>Thorax</i>, <b>29,</b> 475-481. <b>Primary mediastinal tumours.</b> A review of 28 patients with primary mediastinal tumours seen over a five-year period is presented. Clinical and pathological features of a heterogeneous group of tumours are emphasized. Since a number of patients presented with mild symptoms or were asymptomatic (especially adults), the importance of routine chest radiographs is stressed. Complete excision was accomplished in all patients with benign lesions. Malignant lesions were usually partially resectable and carried a poor prognosis.
Inhibition of Thrombin-Activated Fibrinolysis Inhibitor Increases Survival in Experimental Kidney Fibrosis
Authors: John M. Atkinson, Nick Pullen, Michelle Da Silva-Lodge, Lynne Williams, Tim S. Johnson
Journal: Journal of the American Society of Nephrology (2014)

Uncontrolled diabetes, inflammation, and hypertension are key contributors to progressive renal fibrosis and subsequent loss of renal function. Reduced fibrinolysis appears to be a feature of ESRD, but its contribution to the fibrotic program has not been extensively studied. Here, we show that in patients with CKD, the activity levels of serum thrombin-activated fibrinolysis inhibitor and plasmin strongly correlated with the degree of renal function impairment. We made similar observations in rats after subtotal nephrectomy and tested whether pharmacologic inhibition of thrombin-activated fibrinolysis inhibitor with UK-396082 could reduce renal fibrosis and improve renal function. Compared with untreated animals, UK-396082-treated animals had reduced glomerular and tubulointerstitial fibrosis after subtotal nephrectomy. Renal function, as measured by an increase in creatinine clearance, was maintained and the rate of increase in proteinuria was reduced in UK-396082-treated animals. Furthermore, cumulative survival improved from 16% to 80% with inhibition of thrombin-activated fibrinolysis inhibitor. Taken together, these data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for suppression of thrombin-activated fibrinolysis inhibitor activity.
Myeloperoxidase and Protein Oxidation in the Airways of Young Children with Cystic Fibrosis
Authors: Anthony J. Kettle, Timothy Chan, Iris Osberg, Revathy Senthilmohan, Anna L. P. Chapman, Tessa J. Mocatta, Jeffrey S. Wagener
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Cystic fibrosis (CF) is characterized by considerable oxidative stress. However, it is not known whether oxidative stress is an important feature early in this disease. We have investigated a group of infants and young children with CF to establish whether oxidants are produced in their airways. Bronchoalveolar lavage fluid (BALF) was assayed for myeloperoxidase as a measure of neutrophilic inflammation, and 3-chlorotyrosine as a biomarker of the potent oxidant hypochlorous acid, which is formed by myeloperoxidase. Protein carbonyls were also measured as a nonspecific indicator of reactive oxidant production. Myeloperoxidase and 3-chlorotyrosine levels in BALF from children with CF were 10- and fivefold higher, respectively, than in disease control subjects. There was a strong correlation between myeloperoxidase and 3-chlorotyrosine. Myeloperoxidase levels were fourfold higher in children with infections in their airways. Median protein carbonyls were elevated by only twofold compared with disease control subjects, but some children had extremely high levels of protein oxidation. We conclude that hypochlorous acid is produced early in CF and that it is a candidate for precipitating the fatal decline in lung function associated with this disease. Also, there must be other sourcesof oxidants because protein carbonyls were not related to either inflammation or infection.