tbuckley/cabot-search huggingface dataset:
Chromosomal Abnormalities in Patients With Hodgkin's Disease: Evidence for Frequent Involvement of the 14q Chromosomal Region but Infrequent bcl-2 Gene Rearrangement in Reed-Sternberg Cells
Authors: S. Poppema, J. Kaleta, B. Hepperle
Journal: JNCI Journal of the National Cancer Institute (1992)

Background : Rearrangements of the bcl-2 gene (also known as BCL2) have been detected in up to 40% of cases of Hodgkin's disease, and it has been speculated that such rearrangements may have a role in the pathogenesis of Hodgkin's disease. Purpose : The purposes of this study were ( a ) to assess the frequency of clonal chromosomal abnormalities in Hodgkin's disease, ( b ) to identify recurrent changes, ( c ) to determine whether the bcl-2 gene rearrangement was present in Reed-Sternberg cells (the neoplastic cells of Hodgkin's disease) and their variants, and ( d ) to analyze whether the presence of t(14;18) translocations in Reed-Sternberg cells explains the observed bcl-2 gene rearrangements in Hodgkin's disease. Methods : A cytogenetic study was performed on biopsy specimens from 28 consecutive untreated patients with Hodgkin's disease. The same patients were analyzed for bcl-2 gene rearrangement by a polymerase chain reaction (PCR) technique. To ascertain whether the abnormal karyotypes were present in and restricted to Reed-Sternberg cells, we also performed in situ hybridization with chromosome-specific probes. Results : Abnormal metaphases were identified in 23 of the 28 patients. In 11 patients, the chromosome 14q region was abnormal; in six of these patients, there was involvement of the 14q32 region that comprises the gene encoding for heavy-chain immunoglobulin. Only one patient had a t(14;18) translocation, whereas almost 40% of these 28 patients showed bcl-2 gene rearrangements by a PCR method. The in situ hybridization method showed that the abnormal karyotype was present in and restricted to Reed-Sternberg cells. Conclusions : We conclude that the majority of cases of Hodgkin's disease contain a clonal population with an abnormal karyotype, comprising the Reed-Sternberg cells. The q32 region of chromosome 14 is frequently involved, but a t(14;18) translocation is extremely infrequent. The occurrence of a bcl-2 gene rearrangement in Hodgkin's disease most likely results from the presence of sporadic, small bystander B lymphocytes that carry the translocation and that also can be frequently detected in reactive lymphoid tissue such as tonsils. Also, a range of different chromosomal translocations may provide growth or survival advantages to Reed-Sternberg cells. [J Natl Cancer Inst 84:1789–1793, 1992]
Task force says US academic health centres need major changes
Authors: J. Hopkins Tanne
Journal: BMJ (2003)

A US report has called for new sources of financing, increased information technology, and an emphasis on lifetime learning in order to modernise the country's academic health centres. These institutions carry out teaching and research and include not only teaching hospitals but also some networks of primary care doctors and community hospitals.

The report is from the Commonwealth Fund, a private foundation that supports independent research on health and social issues and makes grants to improve healthcare practice and policy.

The fund recommends changes to ensure that academic health centres go on fulfilling their important roles–not only research and training, but also provision of specialised care and treatment …
Obese Women and the Relation Between Cardiovascular Risk Profile and Hormone Therapy, Glucose Tolerance, and Psychosocial Conditions
Authors: Jonas Lidfeldt, Göran Samsioe, Carl-David Agardh
Journal: Diabetes Care (2006)

To evaluate the relation between cardiovascular disease (CVD) risk factors and hormone therapy, serum hormone levels, glucose tolerance, and psychosocial and psychological conditions in subjectively healthy obese female subjects.The study included 606 women, aged 50-64 years, with BMI 30-40 kg/m(2) and no history of cardiovascular or other severe diseases. One group with a CVD risk profile (n = 473) (i.e., cholesterol >7.0 mmol/l, HDL cholesterol <1.2 mmol/l, triglycerides >2.0 mmol/l, systolic or diastolic blood pressure >140/90 mmHg, or waist-to-hip ratio >0.85) was compared with women without such risk (n = 133). Steroid hormones, leptin, insulin, and oral glucose tolerance tests (OGTTs) were analyzed. A subgroup of women with baseline impaired glucose tolerance (IGT) completed a 2.5-year follow-up OGTT.Fewer obese postmenopausal women with CVD risk had ever used hormone therapy (odds ratio 0.24 [95% CI 0.07-0.75]), after multivariate adjustments. Furthermore, women with CVD risk had a higher testosterone index (1.07 [1.01-1.13]) and more had insulin resistance (1.04 [1.00-1.08]) and IGT (2.92 [1.50-5.69]), while OGTT was similar at follow-up. No differences were observed regarding family history or lifestyle, except that fewer women with CVD risk consumed fruits, boiled vegetables, or whole-grain cereals. More women with CVD risk lived alone (3.26 [1.28-8.31]) and had more mental problems (1.16 [1.05-1.28]).Previously healthy obese women with a CVD risk profile seemed to have a high risk of diabetes, as well as psychosocial or psychological problems. Hormone therapy was associated with reduced CVD risk. Obesity's growing burden on society makes it more important to further target individuals that are at greatest risk of future health hazards.
Evolutionary Models Accounting for Layers of Selection in Protein-Coding Genes and their Impact on the Inference of Positive Selection
Authors: N. D. Rubinstein, A. Doron-Faigenboim, I. Mayrose, T. Pupko
Journal: Molecular Biology and Evolution (2011)

The selective forces acting on a protein-coding gene are commonly inferred using evolutionary codon models by contrasting the rate of nonsynonymous substitutions to the rate of synonymous substitutions. These models usually assume that the synonymous substitution rate, Ks, is homogenous across all sites, which is justified if synonymous sites are free from selection. However, a growing body of evidence indicates that the DNA and RNA levels of protein-coding genes are subject to varying degrees of selective constraints due to various biological functions encoded at these levels. In this paper, we develop evolutionary models that account for these layers of selection by allowing for both among-site variability of substitution rates at the DNA/RNA level (which leads to Ks variability among protein-coding sites) and among-site variability of substitution rates at the protein level (Ka variability). These models are constructed so that positive selection is either allowed or not. This enables statistical testing of positive selection when variability at the DNA/RNA substitution rate is accounted for. Using this methodology, we show that variability of the baseline DNA/RNA substitution rate is a widespread phenomenon in coding sequence data of mammalian genomes, most likely reflecting varying degrees of selection at the DNA and RNA levels. Additionally, we use simulations to examine the impact that accounting for the variability of the baseline DNA/RNA substitution rate has on the inference of positive selection. Our results show that ignoring this variability results in a high rate of erroneous positive-selection inference. Our newly developed model, which accounts for this variability, does not suffer from this problem and hence provides a likelihood framework for the inference of positive selection on a background of variability in the baseline DNA/RNA substitution rate.
Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels
Authors: Ralph A. DeFronzo, Muhammad A. Abdul-Ghani
Journal: Diabetes Care (2009)

In their recent study, Utzschneider et al. (1) demonstrated that indexes of insulin secretion and insulin sensitivity derived from plasma glucose and insulin concentration during the oral glucose tolerance test (OGTT) display an inverse relationship similar to that observed with the frequently sampled intravenous glucose tolerance test. Further, the product of the change in insulin divided by change in glucose (ΔI/ΔG) × insulin sensitivity (the insulin secretion/insulin resistance [IS/IR] index or so-called disposition index), which provides an estimate of β-cell function relative to the prevailing level of insulin resistance, was shown to predict the future risk for type 2 diabetes independent of the glucose tolerance status in Japanese-American individuals.

These observations are consistent with previous publications from our lab (2–5) and extend our …
Effects of osmolality on bicarbonate absorption by medullary thick ascending limb of the rat.
Authors: D W Good
Journal: Journal of Clinical Investigation (1992)

Previously we demonstrated that arginine vasopressin (AVP) directly inhibits bicarbonate absorption (JHCO3, pmol/min per mm) in the medullary thick ascending limb (MTAL) of the rat. To determine whether changes in osmolality also may affect bicarbonate absorption, MTAL were studied in vitro with 25 mM HCO3- solutions. Control osmolality was 290 mosmol/kg H2O. In the absence of AVP, increasing osmolality to 560 in perfusate and bath by addition of 150 mM NaCl reduced JHCO3 from 13.7 to 4.5. With 2 x 10(-10) M AVP in the bath, adding 150 mM NaCl to perfusate and bath reduced JHCO3 from 6.9 to 0.6, while adding NaCl to the bath alone reduced JHCO3 from 7.1 to 0.5. Adding 150 mM NaCl to perfusate and bath caused a similar inhibition of JHCO3 in MTAL perfused with furosemide to inhibit net NaCl absorption. In the presence of AVP, adding 600 mM urea to perfusate and bath inhibited JHCO3 by 55%; adding 300 or 600 mM mannitol to perfusate and bath inhibited JHCO3 by 75%. The effects on JHCO3 were reversible and dissociable from changes in transepithelial voltage. Conclusions: (1) osmolality is a factor capable of regulating renal tubule bicarbonate absorption; (2) hypertonicity produced with NaCl, urea, or mannitol markedly inhibits bicarbonate absorption in the MTAL; (3) this inhibition occurs independent of, and is additive to, inhibition by vasopressin. Hypertonicity may shift TAL HCO3- absorption from medulla to cortex, thereby limiting delivery of bicarbonate to the medullary interstitium during antidiuresis.
Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation
Authors: Raphaël F. Rousseau, Ettore Biagi, Aurélie Dutour, Eric S. Yvon, Michael P. Brown, Tiffany Lin, Zhuyong Mei, Bambi Grilley, Edwina Popek, Helen E. Heslop, Adrian P. Gee, Robert A. Krance, Uday Popat, George Carrum, Judith F. Margolin, Malcolm K. Brenner
Journal: Blood (2005)
Artificial Nutrition Support in Clinical Practice, 2nd edn: Edited by J Payne-James, G Grimble, D Silk. Greenwich Medical Media, pound125. ISBN 1-90015-97-9
Authors: J Powell-Tuck
Journal: Gut (2003)

Osteoporosis and liver disease: additional reasons for coeliac disease screeningWe read with great interest the recently published guidelines on the management of osteoporosis associated with chronic liver disease (Gut 2002;50(suppl I):i1-9).However, we would like to add a few words of comment.Associations between coeliac disease (CD) and primary biliary cirrhosis in particular and other autoimmune liver diseases in general have been reported. [1]2][3] In addition, it has been suggested that these individuals should be considered as an at risk group for whom serological testing for CD is indicated. 1Patients with CD are at high risk of developing low bone mineral density and bone turnover impairment, 1 and it has been shown that adherence to a gluten free diet has a significant positive impact on these parameters. 4 Thus we suggest that physicians caring for patients with the above mentioned liver diseases should screen them for CD in the presence of signs and symptoms suggestive of malabsorption such as osteoporosis.This seems a reasonable strategy as detection of CD will allow for a more rational therapeutic approach to the risks determined by this association.Complications due to the presence of CD, such as malnutrition, anaemia, and osteoporosis, may have a considerable impact on liver disease management and the need/success of transplantation.
Effect on Survival of Longer Intervals Between Confirmed Diagnosis and Treatment Initiation Among Low-Income Women With Breast Cancer
Authors: John M. McLaughlin, Roger T. Anderson, Amy K. Ferketich, Eric E. Seiber, Rajesh Balkrishnan, Electra D. Paskett
Journal: Journal of Clinical Oncology (2012)

To determine the impact of longer periods between biopsy-confirmed breast cancer diagnosis and the initiation of treatment (Dx2Tx) on survival.This study was a noninterventional, retrospective analysis of adult female North Carolina Medicaid enrollees diagnosed with breast cancer from January 1, 2000, through December, 31, 2002, in the linked North Carolina Central Cancer Registry-Medicaid Claims database. Follow-up data were available through July 31, 2006. Cox proportional hazards regression models were constructed to evaluate the impact on survival of delaying treatment ≥ 60 days after a confirmed diagnosis of breast cancer.The study cohort consisted of 1,786 low-income, adult women with a mean age of 61.6 years. A large proportion of the patients (44.3%) were racial minorities. Median time from biopsy-confirmed diagnosis to treatment initiation was 22 days. Adjusted Cox proportional hazards regression showed that although Dx2Tx length did not affect survival among those diagnosed at early stage, among late-stage patients, intervals between diagnosis and first treatment ≥ 60 days were associated with significantly worse overall survival (hazard ratio [HR], 1.66; 95% CI, 1.00 to 2.77; P = .05) and breast cancer-specific survival (HR, 1.85; 95% CI, 1.04 to 3.27; P = .04).One in 10 women waited ≥ 60 days to initiate treatment after a diagnosis of breast cancer. Waiting ≥ 60 days to initiate treatment was associated with a significant 66% and 85% increased risk of overall and breast cancer-related death, respectively, among late-stage patients. Interventions designed to increase the timeliness of receiving breast cancer treatments should target late-stage patients, and clinicians should strive to promptly triage and initiate treatment for patients diagnosed at late stage.
Tranquilizer Prescribing as a Function of the Experience and Availability of the Therapist
Authors: WERNER M. MENDEL
Journal: American Journal of Psychiatry (1967)

A two-year study indicated that the more experienced the therapist is, the less he tends to use tranquilizing drugs to manage hospitalized psychotic patients. It was also observed that patients admitted during the weekend, when fewer therapists were available and hence less patient-therapist contact was possible, had a greater chance of receiving a prescription for medication.
The influence of mannitol on myoglobinuric acute renal failure
Authors: R A Zager, C Foerder, C Bredl
Journal: Journal of the American Society of Nephrology (1991)

This study was undertaken to explore the protective influence of mannitol against the glycerol model of myohemoglobinuric acute renal failure. Three hypotheses were tested: (1) mannitol confers cytoprotection by acutely blunting renal hypoperfusion, thereby improving tubular cell energetics; (2) as an hydroxyl radical (OH.) scavenger, mannitol mitigates Fe-driven lipid peroxidation and, hence, decreases tubular cell necrosis; and (3) mannitol prevents intrarenal heme pigment trapping, decreasing cast formation. Rats were injected with 50% glycerol (10 mL/kg im), followed immediately by an iv mannitol (1.25 mL/100 g over 1 h) or sham infusion. Mannitol induced a brisk diuresis (approximately 5.7 mL/2 h; approximately 35 mg of heme protein excreted), whereas glycerol controls were anuric. Mannitol did not significantly increase postglycerol RBF (2.8 mL/min), and it paradoxically worsened cellular energetics, halving cortical ATP concentrations at 1 h. However, this adverse effect on ATP was transient, correlating with active diuresis. Glycerol did not induce convincing in vivo lipid peroxidation (malondialdehyde; conjugated diene assay), and mannitol did not block Fe-driven in vitro lipid peroxidation of isolated brush border membrane vesicles. Na benzoate, an OH. scavenger, conferred no in vivo or in vitro protection. However, Na2SO4, not an OH. scavenger, reproduced the diuretic and in vivo protective effects of mannitol. Purified myoglobin infusion (35 mg) largely negated the beneficial action of mannitol. It was concluded that mannitol confers functional but not cytoprotection against the glycerol acute renal failure model, it acutely worsens renal bioenergetics, and its protective influence is probably due to a diuretic, not an antioxidant, effect.
Biologicals for rheumatoid arthritis
Authors: P. Tugwell, J. A. Singh, G. A. Wells
Journal: BMJ (2011)

#### Case scenario A 45 year old woman had seropositive erosive rheumatoid arthritis diagnosed three years ago with involvement of the hands, wrists, shoulders, and feet. She found it difficult to dress, cook, do the housework, and control her dog on her morning walk. She improved initially on triple disease modifying antirheumatic drug (DMARD) therapy (methotrexate 25 mg intramuscularly weekly with oral folic acid 1 mg daily, hydroxychloroquine 400 mg daily, sulfasalazine 1 g twice daily) and naproxen 500 mg twice daily. Her symptoms have now flared up despite continuation of triple DMARD therapy, with multiple swollen and tender joints. Radiographs show that since last year she has developed three new erosions in her metacarpophalangeal joints. She wants to discuss the new biological drugs that you mentioned would be an option if she did not respond to the above therapy The term biological describes treatments developed and produced in live cell systems. The drugs may also be referred to as biological therapies or cytokine modulators.1 By targeting molecules involved in the inflammatory response, such as tumour necrosis factor-α, some biologicals help to reduce or suppress inflammation, potentially reducing joint damage in rheumatoid arthritis. They are used for an increasing number of indications and are approved in some countries for conditions such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. Most of these conditions are autoimmune diseases characterised by upregulation of cytokines such as interleukins; tumour necrosis factor and T and B lymphocytes contribute to the inflammation, a central pathophysiological feature of these conditions. The following are approved for treatment of rheumatoid arthritis in the United Kingdom or the United States, or both:
The Prolactin/Growth Hormone Receptor Family
Authors: PAUL A. KELLY, JEAN DJIANE, MARIE-CATHERINE POSTEL-VINAY, MARC EDERY
Journal: Endocrine Reviews (1991)

PROLACTIN (PRL), growth hormone (GH), and placental lactogen (PL), or chorionic somatomamotropin (CS) form a family of polypeptide hormones, which, based on amino acid sequence homology, are reported to have arisen by duplication of an ancestral gene (1). Determination of the structure of the genes encoding PRL, GH, and PL has confirmed this theory. PRL and GH are produced by cells of the anterior pituitary gland and are found in all vertebrates, whereas PL or CS is synthesized by the placenta. The initial step in the mechanism of action of PRL and GH is the binding of the respective ligand to a cell surface receptor. Hormone receptors were originally defined as molecules with low capacity and high affinity and specificity for a ligand, the binding of which resulted in a biological response. Many tissues that are not known targets for these hormones contain measurable binding. A number of studies that have appeared in the literature have described PRL binding, without any direct association with a biological response. The fact that ligand binding occurs suggests, but does not necessarily imply, receptor function. The most likely explanation is that PRL and GH cause effects in these tissues that have not yet been determined.
Defining and detecting innovation: Are cognitive and developmental mechanisms important?
Authors: Brooke L. Sargeant, Janet Mann
Journal: Behavioral and Brain Sciences (2007)

Abstract Although the authors' ingenuity in identifying criteria for innovation for field studies is appealing, most field studies will lack adequate data. Additionally, their definition does not clearly distinguish innovation from individual learning and is vague about cognitive mechanisms involved. We suggest that developmental data are essential to identifying the causes and consequences of learning new behaviors.
Dobutamine Increases Alveolar Liquid Clearance in Ventilated Rats by Beta-2 Receptor Stimulation
Authors: FRED A. TIBAYAN, ASHA N. CHESNUTT, HANS G. FOLKESSON, JON EANDI, MICHAEL A. MATTHAY
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Although it is well known that beta-adrenergic agonist stimulation increases alveolar epithelial sodium and fluid transport, it is not known whether the beta-1 or the beta-2 receptor mediates this effect. Two clinically relevant beta-adrenergic agonists, dopamine (beta-1 agonist) and dobutamine (beta-1 and beta-2 agonist) were used to define the contribution of these two beta-receptors to beta-adrenergic stimulated fluid clearance from the air spaces of the lungs. Alveolar fluid clearance was measured in anesthetized, ventilated rats over one hour after instilling an isosmolar 5% albumin solution in Ringer's lactate with 3 μ Ci 125I-albumin. The concentrations of the labeled and unlabeled albumin were used to quantify alveolar liquid clearance. Dopamine, whether given intra-alveolar (10− 4 M) or intravenously (5–10 μ g/kg/min), had no effect. However, both intra-alveolar (10− 4 M) and intravenous (5 μ g/kg/min) dobutamine increased alveolar liquid clearance by approximately 50% over one hour compared to controls. ICI 118,551, a potent and specific beta-2 antagonist, blocked the effect of dobutamine. The dobutamine effect was blocked by amiloride (10− 3 M), an inhibitor of sodium uptake. In summary, the beta-2 receptor mediates beta-adrenergic stimulation of alveolar epithelial sodium and fluid transport.
Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3
Authors: Marina Ostroukhova, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, Anuradha Ray
Journal: Journal of Clinical Investigation (2004)

Under normal circumstances, the respiratory tract maintains immune tolerance in the face of constant antigen provocation. Using a murine model of tolerance induced by repeated exposure to a low dose of aerosolized antigen, we show an important contribution by CD4(+) T cells in the establishment and maintenance of tolerance. The CD4(+) T cells expressed both cell surface and soluble TGF-beta and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice. While cells expressing cell surface TGF-beta were detectable in mice with inflammation, albeit at a lower frequency compared with that in tolerized mice, only those from tolerized mice expressed FOXP3. Blockade of TGF-beta in vitro and in vivo interfered with immunosuppression. Although cells that expressed TGF-beta on the cell surface (TGF-beta(+)), as well as the ones that did not (TGF-beta(-)), secreted equivalent levels of soluble TGF-beta, only the former were able to blunt the development of an allergic phenotype in mice. Strikingly, separation of the TGF-beta(+) cells from the rest of the cells allowed the TGF-beta(-) cells to proliferate in response to antigen. We propose a model of antigen-induced tolerance that involves cell-cell contact with regulatory CD4(+) T cells that coexpress membrane-bound TGF-beta and FOXP3.