tbuckley/cabot-search huggingface dataset:
Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1
Authors: Zhifeng Sun, Paul W. Denton, Jacob D. Estes, Florence A. Othieno, Bangdong L. Wei, Anja K. Wege, Michael W. Melkus, Angela Padgett-Thomas, Mary Zupancic, Ashley T. Haase, J. Victor Garcia
Journal: The Journal of Experimental Medicine (2007)

Intrarectal infection between men who have sex with men represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV infected humans. This novel model provides the basis for the development and evaluation of novel approaches aimed at immune reconstitution of human gut-associated lymphoid tissue and for the development, testing, and implementation of microbicides to prevent intrarectal HIV-1 transmission.
Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis
Authors: Takashi Kokudo, Kiyoshi Hasegawa, Satoshi Yamamoto, Junichi Shindoh, Nobuyuki Takemura, Taku Aoki, Yoshihiro Sakamoto, Masatoshi Makuuchi, Yasuhiko Sugawara, Norihiro Kokudo
Journal: Journal of Hepatology (2014)
The population prevalence of symptomatic radiographic foot osteoarthritis in community-dwelling older adults: cross-sectional findings from the Clinical Assessment Study of the Foot
Authors: Edward Roddy, Martin J Thomas, Michelle Marshall, Trishna Rathod, Helen Myers, Hylton B Menz, Elaine Thomas, George Peat
Journal: Annals of the Rheumatic Diseases (2013)

Objectives To estimate the population prevalence of symptomatic radiographic osteoarthritis (OA) affecting the 1st metatarsophalangeal joint (MTPJ), 1st and 2nd cuneometatarsal joints (CMJs), navicular first cuneiform joint (NCJ) and talonavicular joint (TNJ) in community-dwelling older adults. Methods 9334 adults aged ≥50 years registered with four general practices were mailed a health survey. Responders reporting foot pain within the last 12 months were invited to undergo weight-bearing dorso-plantar and lateral radiographs of both feet. OA at the 1st MTPJ, 1st and 2nd CMJs, NCJ and TNJ was graded using a validated atlas. Population prevalence estimates for symptomatic radiographic foot OA overall and for each joint were calculated using multiple imputation and weighted logistic regression modelling to account for missing data and non-response. Results 5109 health surveys were received (adjusted response 56%). Radiographs were obtained on 557 participants. Overall population prevalence of symptomatic radiographic OA was 16.7% (95% CI 15.3% to 18.0%), 1st MTPJ 7.8% (6.7% to 8.9%), 1st CMJ 3.9% (2.9% to 4.9%), 2nd CMJ 6.8% (5.7% to 7.8%), NCJ 5.2% (4.0% to 6.4%) and TNJ 5.8% (4.8% to 6.9%). With the exception of the 1st CMJ, prevalence was greater in females than males, increased with age and was higher in lower socioeconomic classes. Three-quarters of those with symptomatic radiographic OA reported disabling foot symptoms. Conclusions While cautious interpretation due to non-response is warranted, our study suggests that symptomatic radiographic foot OA affects one in six older adults and the majority report associated disability. Clinicians should consider OA as a possible cause of chronic foot pain in older people.
Gene Transfer of the Serine Elastase Inhibitor Elafin Protects Against Vein Graft Degeneration
Authors: S. B. O'Blenes, S. H. E. Zaidi, A. Y. L. Cheah, B. McIntyre, Y. Kaneda, M. Rabinovitch
Journal: Circulation (2000)

Leukocyte infiltration and serine elastase activity lead to smooth muscle cell proliferation in association with posttransplant coronary arteriopathy and may also be involved in vein graft neointimal formation. A number of therapies have targeted cellular proliferation, but the inhibition of serine elastase-mediated extracellular matrix remodeling has not been investigated as a potential strategy to prevent neointimal formation and subsequent atherosclerotic degeneration in vein grafts.We studied jugular vein grafts 48 hours after interposition into the carotid arteries of rabbits and demonstrated inflammatory cell infiltration and elevated serine elastase activity, a stimulus for matrix remodeling and deposition of elastin. Therefore, elastolytic activity in vein grafts was targeted through transient expression of the selective serine elastase inhibitor elafin with hemagglutinating virus of Japan liposome-mediated gene transfer. Elafin transfection reduced inflammation by 60% at 48 hours and neointimal formation by approximately 50% at 4 weeks after implantation. At 3 months, a 74% decrease in neointimal elastin deposition correlated with protection against cholesterol-induced macrophage infiltration and lipid accumulation, which were both reduced by approximately 50% in elafin-transfected grafts relative to controls.Gene transfer of the selective serine elastase inhibitor elafin in vein grafts is effective in reducing the early inflammatory response. Although transient expression of elafin delays neointimal formation, it is also sufficient to cause an alteration in elastin content of the extracellular matrix, making it relatively resistant to atherosclerotic degeneration.
Central blood volume in cirrhosis: Measurement with radionuclide angiography
Authors: Florence Wong, Peter Liu, Sheldon Tobe, Gilles Morali, Laurence Blendis
Journal: Hepatology (1994)

In patients with cirrhosis a diminished effective central arterial blood volume associated with systemic arterial vasodilation has been proposed as the mechanism that initiates renal sodium retention. Furthermore, total central blood volume has recently been reported as reduced in cirrhosis, and the controversy over the stimulus for sodium retention in cirrhosis remains. The aim of this study was to assess the central blood volume with radionuclide angiography to determine whether there is effective arterial underfilling in cirrhosis. Twenty-nine patients (13 with and 16 without ascites) and 10 age- and sex-matched control subjects were studied under metabolic conditions. Radionuclide ventricular volume and total central blood volume were determined from gated images, taking into account the 99Tc count activity per milliliter of blood volume and attenuation. The pulmonary volumes were similarly derived.(ABSTRACT TRUNCATED AT 250 WORDS)
Nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival for Patients With Locally Advanced Rectal Cancer on the Basis of European Randomized Clinical Trials
Authors: Vincenzo Valentini, Ruud G.P.M. van Stiphout, Guido Lammering, Maria Antonietta Gambacorta, Maria Cristina Barba, Marek Bebenek, Franck Bonnetain, Jean-Francois Bosset, Krzysztof Bujko, Luca Cionini, Jean-Pierre Gerard, Claus Rödel, Aldo Sainato, Rolf Sauer, Bruce D. Minsky, Laurence Collette, Philippe Lambin
Journal: Journal of Clinical Oncology (2011)

The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up.All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms.The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome.The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).
Thermal Dose Is Related to Duration of Local Control in Canine Sarcomas Treated with Thermoradiotherapy
Authors: Donald E. Thrall, Susan M. LaRue, Daohai Yu, Thaddeus Samulski, Linda Sanders, Beth Case, Gary Rosner, Chieko Azuma, Jeannie Poulson, Amy F. Pruitt, Wilma Stanley, Marlene L. Hauck, Laurel Williams, Paul Hess, Mark W. Dewhirst
Journal: Clinical Cancer Research (2005)

To test that prospective delivery of higher thermal dose is associated with longer tumor control duration.122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2-5 CEM43 degrees CT90) or high (20-50 CEM43 degrees CT90) thermal dose in combination with radiotherapy. Most dogs (90%) received four to six hyperthermia treatments over 5 weeks.In the primary analysis, median (95% confidence interval) duration of local control in the low-dose group was 1.2 (0.7-2.1) years versus 1.9 (1.4-3.2) years in the high-dose group (log-rank P = 0.28). The probability (95% confidence interval) of tumor control at 1 year in the low-dose versus high-dose groups was 0.57 (0.43-0.70) versus 0.74 (0.62-0.86), respectively. Using multivariable procedure, thermal dose group (P = 0.023), total duration of heating (P = 0.008), tumor volume (P = 0.041), and tumor grade (P = 0.027) were significantly related to duration of local tumor control. When correcting for volume, grade, and duration of heating, dogs in the low-dose group were 2.3 times as likely to experience local failure.Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription.
Effects of a 20-month cluster randomised controlled school-based intervention trial on BMI of school-aged boys and girls: the HEIA study
Authors: May Grydeland, Mona Bjelland, Sigmund Alfred Anderssen, Knut-Inge Klepp, Ingunn Holden Bergh, Lene Frost Andersen, Yngvar Ommundsen, Nanna Lien
Journal: British Journal of Sports Medicine (2013)

Background School-based interventions that target prevention of overweight and obesity in children have been tested with mixed results. Thus, successful interventions are still called for. The aim of the present study was to investigate effects of a multicomponent school-based intervention programme targeting physical activity, sedentary and dietary behaviours on anthropometric outcomes. Methods A 20-month intervention was evaluated in a cluster randomised, controlled study of 1324 11-year-olds. Outcome variables were body mass index (BMI), BMI-for-age z-score (BMIz), waist circumference (WC), waist-to-height ratio (WTHR) and weight status (International Obesity Task Force's cut-offs). Weight, height and WC were measured objectively; pubertal status was self-reported and parental education was self-reported by the parents. Intervention effects were determined by one-way analysis of covariance and logistic regression, after checking for clustering effects of school, and moderating effects of gender, pubertal status and parental education. Results Beneficial effects were found for BMI (p=0.02) and BMIz (p=0.003) in girls, but not in boys. While a beneficial effect was found for BMI (p=0.03) in participants of parents reporting a high level of education, a negative effect was found for WTHR in participants with parents reporting a low level of education (p=0.003). There were no intervention effects for WC and weight status. Conclusions A multicomponent 20-month school-based intervention had a beneficial effect on BMI and BMIz in adolescent girls, but not in boys. Furthermore, children of higher educated parents seemed to benefit more from the intervention, and this needs attention in future interventions to avoid further increase in social inequalities in overweight and obesity.
A Small Interfering RNA Screen of Genes Involved in DNA Repair Identifies Tumor-Specific Radiosensitization by POLQ Knockdown
Authors: Geoff S. Higgins, Remko Prevo, Yin-Fai Lee, Thomas Helleday, Ruth J. Muschel, Steve Taylor, Michio Yoshimura, Ian D. Hickson, Eric J. Bernhard, W. Gillies McKenna
Journal: Cancer Research (2010)

Abstract The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B) and irradiated normal tissue cells (MRC5). Using γH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA polymerase θ) as a potential tumor-specific target. Subsequent investigations showed that POLQ knockdown resulted in radiosensitization of a panel of tumor cell lines from different primary sites while having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumor-specific radiosensitization. Cancer Res; 70(7); 2984–93
Comparison of Therapeutic Effects and Memory Changes with Bilateral and Unilateral ECT
Authors: J. J. STRAIN, L. BRUNSCHWIG, J. P. DUFFY, D. P. AGLE, A. L. ROSENBAUM, T. G. BIDDER
Journal: American Journal of Psychiatry (1968)

The relative merits of bilateral and unilateral electroconvulsive therapy in the treatment of depressed patients were investigated in a double-blind clinical comparison. Although most patients who received the unilateral mode of treatment experienced significantly less immediate memory loss, they required an average of one more treatment and two additional days of hospitalization, as compared with the bilaterally treated group. In addition, a wide range of responses was evident among individuals within each treatment group. The authors conclude that neither treatment mode is uniformly superior; the choice should be made in each case on the basis of patient needs and available treatment facilities.
Regulation of Dendritic Growth and Remodeling by Rho, Rac, and Cdc42
Authors: Richard Threadgill, Kathryn Bobb, Anirvan Ghosh
Journal: Neuron (1997)

The acquisition of cell type-specific morphologies is a central feature of neuronal differentiation and has important consequences for nervous system function. To begin to identify the underlying molecular mechanisms, we have explored the role of Rho-related GTPases in the dendritic development of cortical neurons. Expression of dominant negative mutants of Rac or Cdc42, the Rho-inhibitory molecule C3 transferase, or the GTPase-activating protein RhoGAP p190 causes a marked reduction in the number of primary dendrites in nonpyramidal (multipolar) neurons and in the number of basal dendrites in neurons with pyramidal morphologies. Conversely, the expression of constitutively active mutants of Rho, Rac, or Cdc42 leads to an increase in the number of primary and basal dendrites. In cortical cultures, as in vivo, dendritic remodeling leads to an apparent transformation from pyramidal to nonpyramidal morphologies over time. Strikingly, this shift in favor of nonpyramidal morphologies is also inhibited by the expression of dominant negative mutants of Cdc42 and Rac and by RhoGAP p190. These observations indicate that Rho, Rac, and Cdc42 play a central role in dendritic development and suggest that differential activation of Rho-related GTPases may contribute to the generation of morphological diversity in the developing cortex.
THE ROLE OF THEhsp90-BASED CHAPERONE SYSTEM IN SIGNAL TRANSDUCTION BY NUCLEAR RECEPTORS AND RECEPTORS SIGNALING VIA MAP KINASE
Authors: William B. Pratt
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract The multicomponent heat-shock protein (hsp) 90–based chaperone system is an ubiquitous protein-folding system in the cytoplasm of eukaryotes. Several signal transduction systems utilize an interaction with hsp90 as an essential component of the signaling pathway. The steroid and dioxin receptors are bound to hsp90 through their hormone-binding domains, and several of them must be bound to hsp90 in order to have a ligand-binding site. The binding of ligands to these receptors promotes their dissociation from hsp90, an event that is the first step in their signaling pathways. Several protein kinases, including the Src and Raf components of the MAP kinase system, are also bound to hsp90. Genetic studies in yeast have demonstrated that hsp90 is required for normal signaling via steroid and dioxin receptors and for the activity of Src in vivo. The hsp90-based chaperone system has been reconstituted from purified components, permitting detailed analysis of the molecular basis of the chaperone's role in signal transduction.
CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia-reperfusion injury in mice
Authors: Osamu Yoshida, Shoko Kimura, Edwin K. Jackson, Simon C. Robson, David A. Geller, Noriko Murase, Angus W. Thomson
Journal: Hepatology (2013)

Hepatic innate immune cells, in particular, interstitial dendritic cells (DCs), regulate inflammatory responses and may promote inherent liver tolerogenicity. After tissue injury, adenosine triphosphate (ATP) is released and acts as a damage-associated molecular pattern that activates innate immune cells by pattern recognition receptors. CD39 (ectonucleoside triphosphate diphosphohydrolase-1) rapidly hydrolyzes extracellular ATP to maintain physiological levels. We hypothesized that CD39 expression on liver DCs might contribute to regulation of their innate immune functions. Mouse liver conventional myeloid DCs (mDCs) were hyporesponsive to ATP, compared with their splenic counterparts. This disparity was ascribed to more efficient hydrolysis of ATP by higher expression of CD39 on liver mDCs. Human liver mDCs expressed greater levels of CD39 than those from peripheral blood. The comparatively high expression of CD39 on liver mDCs correlated strongly with both ATP hydrolysis and adenosine production. Notably, CD39−/− mouse liver mDCs exhibited a more mature phenotype, greater responsiveness to Toll-like receptor 4 ligation, and stronger proinflammatory and immunostimulatory activity than wild-type (WT) liver mDCs. To investigate the role of CD39 on liver mDCs in vivo, we performed orthotopic liver transplantation with extended cold preservation using CD39−/− or WT donor mouse livers. Compared to WT liver grafts, CD39−/− grafts exhibited enhanced interstitial DC activation, elevated proinflammatory cytokine levels, and more-severe tissue injury. Moreover, portal venous delivery of WT, but not CD39−/− liver mDCs, to donor livers immediately post-transplant exerted a protective effect against graft injury in CD39−/− to CD39−/− liver transplantation. Conclusions: These data reveal that CD39 expression on conventional liver mDCs limits their proinflammatory activity and confers protective properties on these important innate immune cells against liver transplant ischemia/reperfusion injury. (Hepatology 2013; 58:2163–2175)
Failure to Recognize Newly Identified Aortic Dilations in a Health Care System With an Advanced Electronic Medical Record
Authors: Jennifer R.S. Gordon
Journal: Annals of Internal Medicine (2009)

Background: Concern is growing about missed test results, but data assessing their effect on patient safety are limited. Objective: To examine the frequency with which computed tomography (CT)–documented dilations of the abdominal aorta are accompanied by evidence in the electronic medical record (EMR) that a clinician recognized the abnormality. Design: Retrospective cohort study. Setting: 2 hospitals in the Veterans Affairs Health Care System. Patients: Patients with new dilations of the abdominal aorta detected on CT performed in 2003. Measurements: Radiology report and EMR evidence that the radiologist notified the clinical service, aneurysm size, and interval between CT and EMR recognition. Results: Computed tomography scans of 4112 patients were reviewed and 440 (11%) aortic dilations were identified, of which 91 were new findings. Radiologists directly notified clinical teams about 5 (5%) new dilations. Clinical teams did not record in the EMR recognition of 53 of 91 (58%) dilations within 3 months of the CT, and 9% of these dilations were 5.5 cm or larger. The median time to recognition of aneurysm in the EMR was 237 days, and no EMR documentation existed for 16 abnormalities (29% of surviving patients) during a mean follow-up of 3.2 years. No evidence indicated that any of the aneurysms ruptured or that patient deaths resulted from the delayed follow-up. Limitation: Clinicians may have recognized some aneurysms but did not document them in the EMR. Conclusion: Clinicians neglect to note a substantial proportion of new aortic dilations in the EMR. The findings highlight the need for better strategies to ensure documentation of follow-up of tests. Primary Funding Source: National Institutes of Health.