tbuckley/cabot-search huggingface dataset:
Combination Therapy with Zidovudine and Didanosine Compared with Zidovudine Alone in HIV-1 Infection
Authors: Ann C. Collier
Journal: Annals of Internal Medicine (1993)

To assess safety, pharmacokinetics, and in-vivo virologic activity of five different combination regimens of zidovudine and didanosine compared with zidovudine alone in patients with human immunodeficiency virus type 1 (HIV-1) infection.Open-label, partially randomized, dose-ranging study.University-affiliated, medical center clinics.A total of 69 patients with HIV-1 infection, CD4+ cell counts fewer than 400 cells/mm3, and fewer than 121 days of previous zidovudine treatment.Fifty-five patients received combination therapy with zidovudine and didanosine, and 14 received zidovudine therapy alone (600 mg/d). Daily dosages in milligrams of zidovudine and didanosine, respectively, in the five combination groups were 150 and 90 mg, 300 and 334 mg, 600 and 334 mg, 300 and 500 mg, and 600 and 500 mg.CD4+ cell counts, HIV-1 RNA titers in plasma, and toxic effects.The combination regimens were associated with higher and more sustained increases in CD4+ cells than zidovudine alone, even after adjustment for initial CD4+ counts and previous zidovudine therapy (P < 0.001). The median increase in CD4+ cell counts was 166 cells/mm3 with combination therapy and 77 cells/mm3 with zidovudine alone (P = 0.001) and did not differ statistically among the five combination regimens. Human immunodeficiency virus type 1 RNA titers in plasma decreased in 15 (83%) of 18 combination-therapy recipients compared with 2 of 7 zidovudine-alone recipients (P = 0.017). No pharmacokinetic interactions were seen between zidovudine and didanosine. Toxicity rates were low among all treatment groups. A greater decrease in hemoglobin levels was seen with the regimen using zidovudine alone (-8 g/L) compared with combination regimens using the same zidovudine dose (-1.5 g/L, P = 0.03).Combination therapy with zidovudine and didanosine produced larger and more sustained increases in CD4+ cell counts, more frequent decreases in plasma HIV-1 RNA titers, and more stable hematologic status than zidovudine therapy alone. The effects of this combination on the progression of HIV disease merit further study, to provide information about clinical outcome, because this was a relatively small study based on surrogate markers of HIV-1 infection.
The 25-Year Cumulative Incidence of Lower Extremity Amputations in People With Type 1 Diabetes
Authors: Karine Sahakyan, Barbara E.K. Klein, Kristine E. Lee, Chelsea E. Myers, Ronald Klein
Journal: Diabetes Care (2011)

OBJECTIVE To examine the 25-year cumulative incidence of lower-extremity amputation (LEA) in people with type 1 diabetes. RESEARCH DESIGN AND METHODS Cumulative incidence of LEA was ascertained in Wisconsin Epidemiologic Study of Diabetic Retinopathy participants (n = 943) using the Kaplan-Meier approach accounting for competing risk of death. Relationships of baseline characteristics with incidence of LEA were explored using a proportional hazards approach with discrete linear regression modeling. RESULTS The overall 25-year incidence of LEA was 10.1%. In multivariate analyses (results reported as odds ratio; 95% CI), being male (3.90; 2.29–6.65), heavy smoking (2.07; 1.11–3.85), having hypertension (3.36; 1.91–5.93), diabetic retinopathy (2.62; 1.13–6.09), neuropathy (1.68; 1.02–2.76), and higher HbA1c (per 1% 1.40; 1.24–1.58) were independently associated with the incidence of LEA. CONCLUSIONS Our results show a high 25-year incidence of LEA and suggest that glycemic control and blood pressure control and preventing heavy smoking may result in reduction in its incidence.
Evidence for the effectiveness of electrophysical modalities for treatment of medial and lateral epicondylitis: a systematic review
Authors: Rudi Dingemanse, Manon Randsdorp, Bart W Koes, Bionka M A Huisstede
Journal: British Journal of Sports Medicine (2013)

Several treatments are available to treat epicondylitis. Among these are instrumental electrophysical modalities, ranging from ultrasound, extracorporeal shock wave therapy (ESWT), transcutaneous electrical nerve stimulation (TENS) to laser therapy, commonly used to treat epicondylitis.To present an evidence-based overview of the effectiveness of electrophysical modality treatments for both medial and lateral epicondylitis (LE).Searches in PubMed, EMBASE, CINAHL and Pedro were performed to identify relevant randomised clinical trials (RCTs) and systematic reviews. Two reviewers independently extracted data and assessed the methodological quality. A best-evidence synthesis was used to summarise the results.A total of 2 reviews and 20 RCTs were included, all of which concerned LE. Different electrophysical regimes were evaluated: ultrasound, laser, electrotherapy, ESWT, TENS and pulsed electromagnetic field therapy. Moderate evidence was found for the effectiveness of ultrasound versus placebo on mid-term follow-up. Ultrasound plus friction massage showed moderate evidence of effectiveness versus laser therapy on short-term follow-up. On the contrary, moderate evidence was found in favour of laser therapy over plyometric exercises on short-term follow-up. For all other modalities only limited/conflicting evidence for effectiveness or evidence of no difference in effect was found.Potential effectiveness of ultrasound and laser for the management of LE was found. To draw more definite conclusions high-quality RCTs examining different intensities are needed as well as studies focusing on long-term follow-up results.
Decreased Serum Levels of Adiponectin Are a Risk Factor for the Progression to Type 2 Diabetes in the Japanese Population
Authors: Makoto Daimon, Toshihide Oizumi, Tamotsu Saitoh, Wataru Kameda, Akihiko Hirata, Hiroshi Yamaguchi, Hiroshi Ohnuma, Masahiko Igarashi, Makoto Tominaga, Takeo Kato
Journal: Diabetes Care (2003)

To examine whether decreased serum levels of adiponectin are an independent risk factor for the progression to type 2 diabetes in a Japanese population.The serum levels of adiponectin and tumor necrosis factor-alpha (TNF-alpha) at baseline (from 1995 to 1997) were evaluated in 1,792 individuals (1,023 women and 769 men, aged 58.5 +/- 12.5 years) from a cohort population (n = 3,706) of the Funagata study. Glucose tolerance was evaluated at baseline and also at 5-year follow-up examinations (n = 978, follow-up rate, 54.6%) according to the 1985 World Health Organization criteria. The correlation of clinical traits with serum levels of adiponectin was examined. The association of the traits with the progression to type 2 diabetes at the 5-year follow-up was also examined.Among the traits examined, the correlation with aging was highest (r = 0.312, P < 0.001). Eighteen subjects with normal glucose tolerance (NGT) developed diabetes, and 709 remained NGT at the 5-year follow-up examinations. The subjects who became diabetic had decreased serum levels of adiponectin (7.29 +/- 2.35 vs. 9.13 +/- 2.35 10 x log microg/ml, P = 0.009). Multiple logistic regression analysis with age, sex, waist-to-hip ratio, and 2-h plasma glucose as the variables revealed that serum adiponectin level (odds ratio [per 0.1 log microg/ml] 0.766, P = 0.029) was an independent risk factor for the progression to type 2 diabetes. The subjects whose serum levels of adiponectin were in the lowest tertile were 9.320 times (95% CI 1.046-83.1) more likely to develop diabetes than those in the highest tertile (P = 0.046).Decreased serum adiponectin level is an independent risk factor for progression to type 2 diabetes.
Ventriculitis due to a hetero strain of vancomycin intermediate Staphylococcus aureus (hVISA): successful treatment with linezolid in combination with intraventricular vancomycin
Authors: F AMOD, I MOODLEY, A PEER, J SUNDERLAND, A LOVERING, M WOOTTON, S NADVI, F VAWDA
Journal: Journal of Infection (2004)
De facto privatization or a renewed role for the EU? Paying for Europe's healthcare infrastructure in a recession
Authors: James Barlow, Jens K Roehrich, Steve Wright
Journal: Journal of the Royal Society of Medicine (2010)

If plans to modernise Europe's healthcare infrastructure are to be sustained, new ways of financing it will have to be found.The PFI model has been seriously derailed by the recession, but new forms of public-private partnershipalready being tried
Increased NOD2-mediated recognition of <i>N</i>-glycolyl muramyl dipeptide
Authors: François Coulombe, Maziar Divangahi, Frédéric Veyrier, Louis de Léséleuc, James L. Gleason, Yibin Yang, Michelle A. Kelliher, Amit K. Pandey, Christopher M. Sassetti, Michael B. Reed, Marcel A. Behr
Journal: The Journal of Experimental Medicine (2009)

Peptidoglycan-derived muramyl dipeptide (MDP) activates innate immunity via the host sensor NOD2. Although MDP is N-acetylated in most bacteria, mycobacteria and related Actinomycetes convert their MDP to an N-glycolylated form through the action of N-acetyl muramic acid hydroxylase (NamH). We used a combination of bacterial genetics and synthetic chemistry to investigate whether N-glycolylation of MDP alters NOD2-mediated immunity. Upon infecting macrophages with 12 bacteria, tumor necrosis factor (TNF) α secretion was NOD2 dependent only with mycobacteria and other Actinomycetes (Nocardia and Rhodococcus). Disruption of namH in Mycobacterium smegmatis obrogated NOD2-mediated TNF secretion, which could be restored upon gene complementation. In mouse macrophages, N-glycolyl MDP was more potent than N-acetyl MDP at activating RIP2, nuclear factor κB, c-Jun N-terminal kinase, and proinflammatory cytokine secretion. In mice challenged intraperitoneally with live or killed mycobacteria, NOD2-dependent immune responses depended on the presence of bacterial namH. Finally, N-glycolyl MDP was more efficacious than N-acetyl MDP at inducing ovalbumin-specific T cell immunity in a model of adjuvancy. Our findings indicate that N-glycolyl MDP has a greater NOD2-stimulating activity than N-acetyl MDP, consistent with the historical observation attributing exceptional immunogenic activity to the mycobacterial cell wall.
Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor–Positive Breast Carcinomas Through Genomic Grade
Authors: Sherene Loi, Benjamin Haibe-Kains, Christine Desmedt, Françoise Lallemand, Andrew M. Tutt, Cheryl Gillet, Paul Ellis, Adrian Harris, Jonas Bergh, John A. Foekens, Jan G.M. Klijn, Denis Larsimont, Marc Buyse, Gianluca Bontempi, Mauro Delorenzi, Martine J. Piccart, Christos Sotiriou
Journal: Journal of Clinical Oncology (2007)

A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed.We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome.Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations.The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.
Comparative genomics and DNA array-based genotyping of pandemic Staphylococcus aureus strains encoding Panton-Valentine leukocidin
Authors: S. Monecke, B. Berger-Bächi, G. Coombs, A. Holmes, I. Kay, A. Kearns, H-J. Linde, F. O'Brien, P. Slickers, R. Ehricht
Journal: Clinical Microbiology and Infection (2006)
A Replication Study and Genome-Wide Scan of Single-Nucleotide Polymorphisms Associated with Pancreatic Cancer Risk and Overall Survival
Authors: Jason A. Willis, Sara H. Olson, Irene Orlow, Semanti Mukherjee, Robert R. McWilliams, Robert C. Kurtz, Robert J. Klein
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To explore the effects of single-nucleotide polymorphisms (SNP) on pancreatic cancer risk and overall survival (OS). Experimental Design: The germ line DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on OS. Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Finally, we conducted a genome-wide association study (GWAS) of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively. Results: Among seven risk SNPs analyzed, two (rs505922 and rs9543325) were associated with risk (P &amp;lt; 0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (P &amp;lt; 0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Furthermore, our GWAS identified a novel SNP [rs1482426, combined stage I and II, P = 1.7 × 10−6, per-allele HR, 1.74; 95% confidence interval (CI), 1.38–2.18] to be putatively associated with OS. Conclusions: The effects of SNPs on pancreatic cancer risk and OS were replicated in our study, although further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer. Clin Cancer Res; 18(14); 3942–51. ©2012 AACR.
Rare Variation Facilitates Inferences of Fine-Scale Population Structure in Humans
Authors: Timothy D. O’Connor, Wenqing Fu, Josyf C. Mychaleckyj, Benjamin Logsdon, Paul Auer, Christopher S. Carlson, Suzanne M. Leal, Joshua D. Smith, Mark J. Rieder, Michael J. Bamshad, Deborah A. Nickerson, Joshua M. Akey
Journal: Molecular Biology and Evolution (2014)

Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European–American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies.
Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension
Authors: Jean-Luc Cracowski, François Chabot, José Labarère, Patrice Faure, Bruno Degano, Carole Schwebel, Ari Chaouat, Martine Reynaud-Gaubert, Claire Cracowski, Olivier Sitbon, Azzedine Yaici, Gerald Simonneau, Marc Humbert
Journal: European Respiratory Journal (2013)

Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertensionTo the
Qualitative Assessment of the Progesterone Receptor and HER2 Improves the Nottingham Prognostic Index Up to 5 Years After Breast Cancer Diagnosis
Authors: Vanya Van Belle, Ben Van Calster, Olivier Brouckaert, Isabelle Vanden Bempt, Saskia Pintens, Vernon Harvey, Paula Murray, Björn Naume, Gro Wiedswang, Robert Paridaens, Philippe Moerman, Frederic Amant, Karin Leunen, Ann Smeets, Maria Drijkoningen, Hans Wildiers, Marie-Rose Christiaens, Ignace Vergote, Sabine Van Huffel, Patrick Neven
Journal: Journal of Clinical Oncology (2010)

Purpose To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). Patients and Methods The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. Results In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer–related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI − PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. Conclusion The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.
Incidence, Location, Pathology, and Significance of Pulmonary Homograft Stenosis After the Ross Operation
Authors: G S Carr-White, P J Kilner, J K Hon, T Rutledge, S Edwards, E D Burman, D J Pennell, M H Yacoub
Journal: Circulation (2001)

The Ross operation has several theoretical advantages. However, concern exists regarding evolving pathology in the pulmonary homograft.Consecutive patients (n=144; mean age 31 years, range 2 months to 64 years) undergoing the Ross operation were studied between 1993 and 2000. Echocardiographic examination of the pulmonary homograft was performed immediately after surgery, then at yearly intervals for a mean interval of 48 months. Fifteen patients (mean age 37 years) in whom echocardiography revealed peak pulmonary gradients >/=30 mm Hg (mean 46+/-18 mm Hg) underwent MRI with velocity mapping in a Picker 1.5-T magnet. No patient had more than mild pulmonary regurgitation. Four patients required reoperation for rapidly progressive pulmonary homograft stenosis; in all 4, there was macroscopic and microscopic evidence of a pronounced chronic adventitial reaction, with perivascular infiltration producing extrinsic compression. Freedom from any pulmonary homograft stenosis at 7-year follow-up was 79.7%, with instantaneous hazard falling to zero after 4 years. Freedom from reoperation at 7 years was 96.7%. In those studied with MRI, there was evidence of narrowing of the whole homograft or distal suture line in 14 of 15 patients, with obvious excess surrounding tissue in 11. Mean minimum diameter and peak velocity by MRI were 11+/-2 mm and 3.2+/-0.7 m/s, respectively. Multivariate analysis of patient-, surgery-, and homograft-related variables did not reveal any significant risk factors for development of neopulmonary stenosis.Pulmonary homograft stenosis after the Ross operation is clinically important and appears to represent an early postoperative inflammatory reaction to the pulmonary homograft that leads to extrinsic compression and/or shrinkage.
Local delivery of a collagen-binding FGF-1 chimera to smooth muscle cells in collagen scaffolds for vascular tissue engineering
Authors: Yonggang Pang, Xiaoli Wang, Areck A. Ucuzian, Eric M. Brey, Wilson H. Burgess, Kathryn J. Jones, Thomas D. Alexander, Howard P. Greisler
Journal: Biomaterials (2009)
Scarring alopecia in discoid lupus erythematosus
Authors: C.L. WILSON, S.M. BURGE, D. DEAN, R.P.R. DAWBER
Journal: British Journal of Dermatology (1992)

The clinicopathological features of the scarring alopecia of discoid lupus erythematosus (DLE) were studied. Scarring alopecia was present in 34% of 89 patients with DLE and was associated with a prolonged disease course. More than half these patients had scalp involvement at the onset of the disease. There was a significant reduction in size of sebaceous glands in affected scalp. Perifollicular lymphocytic inflammation was maximal around the mid‐follicle at the level of the sebaceous gland, which seems to be an important functional level in the follicle. There are changes in the expression of the matrix molecules, the proteoglycans, in the connective tissue sheath and the keratin intermediate filaments in the outer root sheath cells at this level in normal scalp and in diseased scalp. Loss of a population of mid‐follicular stem cells may be important in the pathogenesis of scarring alopecia in DLE.
Trafficking to the Apical and Basolateral Membranes in Polarized Epithelial Cells
Authors: Emily H. Stoops, Michael J. Caplan
Journal: Journal of the American Society of Nephrology (2014)

Renal epithelial cells must maintain distinct protein compositions in their apical and basolateral membranes in order to perform their transport functions. The creation of these polarized protein distributions depends on sorting signals that designate the trafficking route and site of ultimate functional residence for each protein. Segregation of newly synthesized apical and basolateral proteins into distinct carrier vesicles can occur at the trans-Golgi network, recycling endosomes, or a growing assortment of stations along the cellular trafficking pathway. The nature of the specific sorting signal and the mechanism through which it is interpreted can influence the route a protein takes through the cell. Cell type–specific variations in the targeting motifs of a protein, as are evident for Na,K-ATPase, demonstrate a remarkable capacity to adapt sorting pathways to different developmental states or physiologic requirements. This review summarizes our current understanding of apical and basolateral trafficking routes in polarized epithelial cells.