tbuckley/cabot-search huggingface dataset:
In vivo silencing of alpha-synuclein using naked siRNA
Authors: Jada Lewis, Heather Melrose, David Bumcrot, Andrew Hope, Cynthia Zehr, Sarah Lincoln, Adam Braithwaite, Zhen He, Sina Ogholikhan, Kelly Hinkle, Caroline Kent, Ivanka Toudjarska, Klaus Charisse, Ravi Braich, Rajendra K Pandey, Michael Heckman, Demetrius M Maraganore, Julia Crook, Matthew J Farrer
Journal: Molecular Neurodegeneration (2008)

Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.
Additional Chenodiol Therapy After Partial Dissolution of Gallstones with Two Years of Treatment
Authors: JAY W. MARKS
Journal: Annals of Internal Medicine (1984)

During the National Cooperative Gallstone Study, therapy with chenodiol, 750 or 375 mg/d, for 2 years resulted in confirmed, complete gallstone dissolution in 14% and 5% of patients, respectively, and partial dissolution (> 50%) in 27% and 18%. The present study was done to determine the frequency with which complete dissolution occurs in patients having partial dissolution of gallstones who receive additional therapy. Eighty-six of one hundred thirty-eight eligible patients continued to receive 750 mg/d (61 patients) or 375 mg/d (25 patients) of chenodiol for 1 year. Patients whose oral cholecystogram at the end of the year showed further (> 50%) dissolution continued to receive chenodiol (28 patients at 750 mg/d and 11 patients at 375 mg/d) for a second year (total duration of therapy, 4 years). A final oral cholecystogram was taken at the end of the fourth year. Complete dissolution occurred in 23% and 16% of patients receiving chenodiol, 750 or 375 mg/d, respectively, for an additional 1 or 2 years.
Evolutionary Dynamics and Evolutionary History in the RTE Clade of Non-LTR Retrotransposons
Authors: Vera Župunski, Franc Gubenšek, Dušan Kordis
Journal: Molecular Biology and Evolution (2001)

This study examined the evolutionary dynamics of Bov-B LINEs in vertebrates and the evolution of the RTE clade of non-LTR retrotransposons. The first full-length reptilian Bov-B LINE element is described; it is 3.2 kb in length, with a structural organization typical of the RTE clade of non-LTR retrotransposons. The long-term evolution of Bov-B LINEs was studied in 10 species of Squamata by analysis of a PCR-amplified 1.8-kb fragment encoding part of apurinic/apyrimidinic endonuclease, the intervening domain, and the palm/fingers subdomain of reverse transcriptase. A very high level of conservation in Squamata Bov-B long interspersed nuclear elements has been found, reaching 86% identity in the nearly 600 amino acids of ORF2. The same level of conservation exists between the ancestral snake lineage and Ruminantia. Such a high level is exceptional when compared with the level of conservation observed in nuclear and mitochondrial proteins and in other transposable elements. The RTE clade has been found to be much more widely distributed than previously thought, and novel representatives have been discovered in plants, brown algae, annelids, crustaceans, mollusks, echinoderms, and teleost fishes. Evolutionary relationships in the RTE clade were deduced at the amino acid level from three separate regions of ORF2. By using different independent methods, including the divergence-versus-age analysis, several examples of horizontal transfer in the RTE clade were recognized, with important implications for the existence of HT in non-LTR retrotransposons.
Histopathologic Subsets of Fibrosing Alveolitis in Patients with Systemic Sclerosis and Their Relationship to Outcome
Authors: Demosthenes Bouros, Athol U. Wells, Andrew G. Nicholson, Thomas V. Colby, Vlasis Polychronopoulos, Panos Pantelidis, Patricia L. Haslam, Dimitris A. Vassilakis, Carol M. Black, Roland M. du Bois
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Fibrosing alveolitis associated with systemic sclerosis (FASSc) has a better prognosis than idiopathic pulmonary fibrosis. In view of recent reports that idiopathic nonspecific interstitial pneumonia (NSIP) has a better prognosis than idiopathic usual interstitial pneumonia (UIP), we classified histologic appearances of surgical lung biopsies performed in 80 patients with FASSc. NSIP (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47) was much more prevalent than UIP (n = 6), end-stage lung disease (ESL, n = 6), or other patterns (n = 6). There were 25 deaths (NSIP 16/62, 26%; UIP/ESL 6/12, 50%). Five-year survival differed little between NSIP (91%) and UIP/ESL (82%); mortality was associated with lower initial carbon monoxide diffusing capacity (DlCO) and FVC levels (p = 0.004 and p = 0.007, respectively). Survival and serial FVC and DlCO trends did not differ between cellular and fibrotic NSIP. Increased mortality in NSIP was associated with lower initial DlCO levels (p = 0.04), higher BAL eosinophil levels (p = 0.03), and deterioration in DlCO levels during the next 3 years (p < 0.005). We conclude that NSIP is the histopathologic pattern in most patients with FASSc. However, outcome is linked more strongly to disease severity at presentation and serial DlCO trends than to histopathologic findings.
Anatomical location of athletic injuries during training: a prospective two year study in 2701 athletes
Authors: J A Sanchis-Gimeno, E Casas-Roman, C Garcia-Campero, R Hurtado-Fernandez, L Aparicio-Bellver
Journal: British Journal of Sports Medicine (2005)

In a review of risk factors for lower extremity injury,1 it was said that alignment of the hip, knee, and ankle has received substantial interest as a potential risk factor. We aimed to quantify the anatomical location of athletic injuries produced during training in order to confirm whether lower extremity injuries are the most common. A second aim was to detect if the knee was …
GPs' undocumented work has increased substantially
Authors: S. J Taylor
Journal: BMJ (2002)

EDITOR—Thinking about my own practice (five doctors, rural market town), I can understand how Florin and Gillam's conclusion that there is no clear evidence that the workload of general practitioners has increased recently can come about.1 Over the past 15 years our list size has remained fairly constant and our home visits and the number of people we have seen have been about the same each year. But we have given up overnight work (the “night visit” rate had increased from one or …
Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study
Authors: Zheng Ye, Stephen J Sharp, Stephen Burgess, Robert A Scott, Fumiaki Imamura, Claudia Langenberg, Nicholas J Wareham, Nita G Forouhi
Journal: The Lancet Diabetes & Endocrinology (2014)

BackgroundLow circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach.MethodsUsing several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes.FindingsAll four SNPs were associated with 25(OH)D concentrations (p<10−6). The mendelian randomisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 (95% CI 0·75–1·36; p=0·94) per 25·0 nmol/L (1 SD) lower 25(OH)D concentration. The corresponding (potentially confounded) relative risk from the meta-analysis of data from observational studies was 1·21 (1·16–1·27; p=7·3 × 10−19). The mendelian randomisation-derived estimates for glycaemic traits were not significant (p>0·25).InterpretationThe association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes.FundingUK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme.
Modulators of crescentic glomerulonephritis.
Authors: R C Atkins, D J Nikolic-Paterson, Q Song, H Y Lan
Journal: Journal of the American Society of Nephrology (1996)

Glomerular crescent formation is a prominent feature of aggressive forms of glomerulonephritis and is associated with a poor prognosis. An understanding of the mechanisms involved in crescent formation is crucial for the development of new therapies for this disease. This article reviews current ideas on the pathogenesis of glomerular crescent formation and describes methods for modulation of this process. Emphasis is given to the role of the proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha in crescent development and its modulation by cytokine blockade.
Magnetic Resonance Imaging of the Breast Prior to Biopsy
Authors: David A. Bluemke
Journal: JAMA (2004)

ContextBreast magnetic resonance imaging (MRI) has been shown to have high sensitivity for cancer detection and is increasingly used following mammography to evaluate suspicious breast lesions.ObjectiveTo determine the accuracy of breast MRI in conjunction with mammography for the detection of breast cancer in patients with suspicious mammographic or clinical findings.Design, Setting, and PatientsProspective multicenter investigation of the International Breast MR Consortium conducted at 14 university hospitals in North America and Europe from June 2, 1998, through October 31, 2001, of 821 patients referred for breast biopsy for American College of Radiology category 4 or 5 mammographic assessment or suspicious clinical or ultrasound finding.InterventionsMRI examinations performed prior to breast biopsy; MRI results were interpreted at each site, which were blinded to pathological results.Main Outcome MeasuresArea under the receiver operating characteristic curve (AUC), sensitivity, and specificity of breast MRI.ResultsAmong the 821 patients, there were 404 malignant index lesions, of which 63 were ductal carcinoma in situ (DCIS) and 341 were invasive carcinoma. Of the 417 nonmalignant index lesions, 366 were benign, 47 showed atypical histology, and 4 were lobular carcinoma in situ. The AUC pooled over all institutions was 0.88 (95% confidence interval [CI], 0.86-0.91). MRI correctly detected cancer in 356 of 404 cancer cases (DCIS or invasive cancer), resulting in a sensitivity of 88.1% (95% CI, 84.6%-91.1%), and correctly identified as negative for cancer 281 of 417 cases without cancer, resulting in a specificity of 67.7% (95% CI, 62.7%-71.9%). MRI performance was not significantly affected by mammographic breast density, tumor histology, or menopausal status. The positive predictive values for 356 of 492 patients was 72.4% (95% CI, 68.2%-76.3%) and of mammography for 367 of 695 patients was 52.8% (95% CI, 49.0%-56.6%) (P<.005). Dynamic MRI did not improve the AUC compared with 3-dimensional MRI alone, but the specificity of a washout pattern for 123 of 136 patients without cancer was 90.4% (95% CI, 84%-95%).ConclusionsBreast MRI has high sensitivity but only moderate specificity independent of breast density, tumor type, and menopausal status. Although the positive predictive value of MRI is greater than mammography, MRI does not obviate the need for subsequent tissue sampling in this setting.
Effect of plant sterols in combination with other cholesterol-lowering foods
Authors: David J.A. Jenkins, Cyril W.C. Kendall, Tri H. Nguyen, Augustine Marchie, Dorothea A. Faulkner, Christopher Ireland, Andrea R. Josse, Edward Vidgen, Elke A. Trautwein, Karen G. Lapsley, Candice Holmes, Robert G. Josse,, Lawrence A. Leiter, Philip W. Connelly, William Singer
Journal: Metabolism (2007)
Combination Chemotherapy for Metastatic Breast Cancer: Reaching for the Cure
Authors: Beth Overmoyer
Journal: Journal of Clinical Oncology (2003)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.10.085 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12586790 Combination Chemotherapy for Metastatic Breast Cancer: Reaching for the Cure Beth OvermoyerxBeth OvermoyerSearch for articles by this author Show More University Hospitals of Cleveland, Case Western Reserve University https://doi.org/10.1200/JCO.2003.10.085 First Page Full Text PDF Figures and Tables © 2003 by American Society of Clinical Oncology
EVALUATION OF COMBINED ANTIDEPRESSANT AND TRANQUILIZING DRUG (AMITRIPTYLINE-PERPHENAZINE) IN THE TREATMENT OF HOSPITALIZED CHRONIC SCHIZOPHRENIC PATIENTS
Authors: ISMET KARACAN, FRANK JONES, ISMAIL ERSEVIM
Journal: American Journal of Psychiatry (1963)

Nineteen hospitalized, chronic female schizophrenics were treated with combined amitriptyline-perphenezine for a period of 12 weeks. Patients were evaluated initially and during the study in terms of standard rating scales, ward behavior, and global clinical judgment. Observations and test data indicate that the patients as a group showed improvement, and the combination of amitriptyline- perphenezine seems compatible. However, since this pilot study did not include a placebo control, no definite conclusion can be drawn at this time. The results are sufficiently encouraging to warrant controlled clinical trial.
Association Between Genetic Polymorphisms in the Prostate-Specific Antigen Gene Promoter and Serum Prostate-Specific Antigen Levels
Authors: S. D. Cramer, B.-L. Chang, A. Rao, G. A. Hawkins, S. L. Zheng, W. N. Wade, R. T. Cooke, L. N. Thomas, E. R. Bleecker, W. J. Catalona, D. A. Sterling, D. A. Meyers, J. Ohar, J. Xu
Journal: JNCI Journal of the National Cancer Institute (2003)

Recent evidence suggests that genetic variation in the promoter of the prostate-specific antigen (PSA) gene may contribute to individual variation in serum PSA levels. However, polymorphisms associated with variations in PSA levels have not been identified.We used the polymerase chain reaction to amplify the promoter region of the PSA genes (nucleotide positions -3873 to -5749 with respect to the start of transcription) of 409 healthy white men at risk for lung disease. Polymerase chain reaction products were sequenced to identify polymorphisms in the PSA gene promoter and to genotype the men for common single nucleotide polymorphisms (SNPs) and were cloned into luciferase reporter constructs to assay PSA promoter activity in human LNCaP prostate cancer cells. Analysis of variance was used to test the association of polymorphism frequencies with mean serum PSA levels. All statistical tests were two-sided.The -4643G/A SNP (G allele) had a 21.2% prevalence and was associated with increases in serum PSA levels (P =.017) and PSA promoter activity (P<.001). The -5412C/T SNP (C allele) had a 22.0% prevalence and was associated with an increase in serum PSA levels (P =.0015). The -5429T/G SNP (G allele) had a 23.0% prevalence, was associated with an increase in serum PSA levels (P =.021), and was in linkage disequilibrium with the -5412C/T SNP. The promoter activity of the -5412 C/-5429 G haplotype was higher than that of the -5412 T/-5429 T haplotype (P<.001).Genetic variations in the PSA promoter are associated with serum PSA levels in men without prostatic disease. PSA promoter genotype information may help to refine models of PSA cutoff values.
Maternal Smoking During Pregnancy and Attention Deficit Hyperactivity Disorder Symptoms in Offspring
Authors: Anita Thapar, Tom Fowler, Frances Rice, Jane Scourfield, Marianne van den Bree, Hollie Thomas, Gordon Harold, Dale Hay
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The aim of this study was to examine whether smoking during pregnancy is associated with symptoms of attention deficit hyperactivity disorder (ADHD) in offspring and whether these effects are additional to genetic influences. METHOD: Children’s ADHD symptoms (parent- and teacher-rated), maternal smoking during pregnancy, conduct disorder symptoms, and family adversity were assessed with questionnaires for a population-based sample of twins (1,452 twin pairs 5–16 years of age). RESULTS: Although genetic influences accounted for most of the variance in offspring ADHD, maternal smoking during pregnancy was still found to show a significant environmentally mediated association. Maternal smoking remained a significant influence when other potential confounds were taken into account. CONCLUSIONS: Maternal smoking during pregnancy appears to show an association with offspring ADHD symptoms that is additional to the effects of genes and not attributable to shared rater effects, clinical referral biases, or covariation with antisocial behavior.
A Low-Glycemic Load Diet Facilitates Greater Weight Loss in Overweight Adults With High Insulin Secretion but Not in Overweight Adults With Low Insulin Secretion in the CALERIE Trial
Authors: Anastassios G. Pittas, Sai Krupa Das, Cheryl L. Hajduk, Julie Golden, Edward Saltzman, Paul C. Stark, Andrew S. Greenberg, Susan B. Roberts
Journal: Diabetes Care (2005)

Lifestyle changes, in particular reducing energy intake, are the cornerstone of current approaches to weight loss and prevention of type 2 diabetes. However, there is currently no consensus that one dietary regimen is more effective than another for weight loss (1) or whether particular diets work better for identifiable groups of individuals. There is evidence, however, to suggest that both insulin resistance and insulin secretion play a role in body weight regulation (2–12). Therefore, dietary factors such as the dietary glycemic load (glycemic load = glycemic index [GI] × available carbohydrate amount) that influence these parameters may theoretically interact with subject-specific characteristics of glucose-insulin dynamics to influence the effect of different hypocaloric diets on weight loss or maintenance (13,14). Weight loss studies using the concept of the dietary glycemic index or glycemic load have shown conflicting results for heterogeneous groups of individuals (15–21).

In a 6-month controlled feeding trial in healthy overweight adults with normal glucose tolerance, we tested the hypothesis that individuals with higher insulin secretion lose more weight when randomized to a low–glycemic load diet compared with a high–glycemic load diet.

This study was performed as part of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial at the Human Nutrition Research Center on Aging at Tufts University with approval from the Tufts-New England Medical Center Human Investigation Review Committee. Written informed consent was obtained from all participants. Healthy women and men aged 24–42 …
A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer
Authors: I. Chau, A.R. Norman, D. Cunningham, D. Tait, P.J. Ross, T. Iveson, M. Hill, T. Hickish, F. Lofts, D. Jodrell, A. Webb, J.R. Oates
Journal: Annals of Oncology (2005)
ON THE ROLE OF THE RESPONSE OF THE CELL MEMBRANE IN DETERMINING VIRUS VIRULENCE
Authors: Kathryn V. Holmes, Purnell W. Choppin
Journal: The Journal of Experimental Medicine (1966)

The simian myxovirus SV5 multiplies in a continuous line of baby hamster kidney (BHK21-F) cells causing extensive cell fusion, followed by cell death. After inoculation of 15 PFU/cell, the latent period was 7 hr, the doubling time approximately 60 min, and the yield 7 PFU per cell. Giant cell formation began about 6 hr after infection and rapidly progressed to the formation by 14 to 18 hr of a single syncytium which disintegrated by 24 to 36 hr. In contrast, SV5 multiplies in primary rhesus monkey kidney cells for long periods of time producing high yields of virus with little cytopathic effect. High multiplicities of SV5 induced cell fusion in BHK21-F cells within 1 hr in the absence of virus multiplication but had no visible effect on monkey kidney cells. Time-lapse photomicrography has demonstrated that giant cells form by fusion of infected cells, and that some polykaryocytes divide. During aberrant division of polykaryocytes giant nuclei are formed from the nuclear material of several parent nuclei. The cytoplasmic development of viral antigens as demonstrated by immunofluorescence is similar in BHK21-F and monkey kidney cells. Synthesis of cellular DNA, RNA, and protein in monkey kidney cells is not shut off by SV5-infection, and in BHK21-F cells synthesis of these macromolecules is not inhibited until after extensive cell fusion has occurred 12 to 15 hr after infection. Persistently infected BHK21-F and monkey kidney cells have been serially carried through 11 and 28 cell passages, respectively. The results suggest that whether SV5 acts as a moderate virus, as in monkey kidney cells, or a virulent virus, as in BHK21-F cells, depends on the response of the cell membrane to the virus.