tbuckley/cabot-search huggingface dataset:
Risk of Incremental Toxicities and Associated Costs of New Anticancer Drugs: A Meta-Analysis
Authors: Saroj Niraula, Eitan Amir, Francisco Vera-Badillo, Bostjan Seruga, Alberto Ocana, Ian F. Tannock
Journal: Journal of Clinical Oncology (2014)

Purpose There are increasing reports of rare but serious toxicities caused by new anticancer drugs, and there are costs associated with their management. Methods We identified anticancer drugs approved by the US Food and Drug Administration from 2000 to 2011 and pivotal trials supporting their registration. Twelve frequent grade 3 to 4 adverse event (AEs) were weighted and pooled in a meta-analysis. Estimates of incremental drug prices and incremental costs for management of AEs were calculated according to type of new agent based on target specificity. Results We identified 41 studies comprising 27,539 patients and evaluating 19 experimental drugs. Agents directed against a specific molecular target on cancer cells had a lower incidence of grade 3 to 4 toxicities compared with controls (median risk ratio [RR], 0.67; P = .22), whereas less-specific targeted agents, including angiogenesis inhibitors (median RR, 3.39; P &lt; .001) and chemotherapeutic agents (median RR, 1.73; P &lt; .001), were more toxic. Risk was increased regardless of whether the control arm contained active treatment (RR, 2.11; P &lt; .001) or not (RR, 3.02; P &lt; .001). Median incremental drug price for experimental agents was $6,000 per patient per month. Median cost of managing toxicity was low compared with drug costs but higher than controls for treatment with less-specific targeted agents and chemotherapies. Conclusion Newly approved anticancer drugs are associated with increased toxicity, except for agents with a specific molecular target on cancer cells. Management of toxicity leads to a small increase in overall cost of treatment. Frequency of toxicity and associated costs are likely higher in less-selected patients treated in general oncologic practice. Development of biomarker-driven agents should be encouraged.
Small leucine rich proteoglycans (SLRP's) expression in skin, tendons and capsules of athletic population after shoulder dislocation and ACL injuries
Authors: M A Akhtar, T G Ingman, C M Robinson, J F Keating, A Y Muir, H Simpson, D Salter
Journal: British Journal of Sports Medicine (2011)

Introduction Cruciate ligament ruptures and shoulder dislocations are often caused by trauma, but predisposing intrinsic factors might also influence the risk. Decorin and biglycan are members of the small leucine rich proteoglycans (SLRP's) family which are important constituents of interstitial extracellular matrices (ECM) and play important roles in the regulation of collagen fibrillogenesis. Their deficiency could influence wound healing and integrity of skin and muscle. The aim of this study was to localise Decorin and Biglycan in skin, hamstring tendons and shoulder capsules. Patients and methods Localisation of decorin and biglycan was studied by immunohistochemical staining of paraffin embedded sections of skin, tendons and capsules of the patients attending for shoulder stabilisation or anterior cruciate ligament (ACL) reconstruction between November 2008 and July 2009. Results 40 patients were studied, 25 undergoing primary ACL reconstruction and 15 undergoing shoulder stabilisation. The mean age of patients was 26 years. 34 patients (85%) were male and 6 female (15%). Most common sport played was football in 13 patients (32%) followed by rugby in 10 (25%) and skiing in 5 (12%). Skin epidermis, blood vessels, sweat glands, sebaceous glands and arrector pilli stained negative but dermis stained positive to varying degrees for decorin. Synovial surface of the capsule, blood vessels and skeletal muscles stained negative but ECM was positive to varying degrees for decorin. Tendon sheath and collagen fibres in ECM stained positive to varying degrees but skeletal muscle stained negative for decorin. Skin epidermis, blood vessels, sweat glands, sebaceous glands and arrector pilli and dermis stained positive for biglycan to varying degrees. Synovial surface of the capsule, blood vessels and ECM stained positive for biglycan to varying degrees. Tendon sheath stained negative but collagen fibres, blood vessels and skeletal muscles stained positive for biglycan to varying degrees. Discussion We looked at the expression and distribution of decorin and biglycan in skin, tendons and capsules of patients undergoing shoulder stabilisation or ACL reconstruction following sports injuries. There may be a link in the distribution of these SLRP's and strength of tissues, which can predispose individuals to injuries while playing sports and can also affect healing process. Further studies are needed to study this link.
A genome-wide view of mutation rate co-variation using multivariate analyses
Authors: Guruprasad Ananda, Francesca Chiaromonte, Kateryna D Makova
Journal: Genome biology (2011)

While the abundance of available sequenced genomes has led to many studies of regional heterogeneity in mutation rates, the co-variation among rates of different mutation types remains largely unexplored, hindering a deeper understanding of mutagenesis and genome dynamics. Here, utilizing primate and rodent genomic alignments, we apply two multivariate analysis techniques (principal components and canonical correlations) to investigate the structure of rate co-variation for four mutation types and simultaneously explore the associations with multiple genomic features at different genomic scales and phylogenetic distances. We observe a consistent, largely linear co-variation among rates of nucleotide substitutions, small insertions and small deletions, with some non-linear associations detected among these rates on chromosome X and near autosomal telomeres. This co-variation appears to be shaped by a common set of genomic features, some previously investigated and some novel to this study (nuclear lamina binding sites, methylated non-CpG sites and nucleosome-free regions). Strong non-linear relationships are also detected among genomic features near the centromeres of large chromosomes. Microsatellite mutability co-varies with other mutation rates at finer scales, but not at 1 Mb, and shows varying degrees of association with genomic features at different scales. Our results allow us to speculate about the role of different molecular mechanisms, such as replication, recombination, repair and local chromatin environment, in mutagenesis. The software tools developed for our analyses are available through Galaxy, an open-source genomics portal, to facilitate the use of multivariate techniques in future large-scale genomics studies.
Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion.
Authors: W C Gelderblom, S Abel, C M Smuts, J Marnewick, W F Marasas, E R Lemmer, D Ramljak
Journal: Environmental Health Perspectives (2001)

We review the hepatocarcinogenic effects of fungal cultures of Fusarium verticillioides(= Fusarium moniliforme) strain MRC 826 in male BD IX rats. Subsequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB1 provide information about dose-response effects, relevance of hepatotoxicity during FB1-induced carcinogenesis, and the existence of a no-effect threshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body weight (bw)/day over approximately 2 years produce liver cancer in male BD IX rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, although mild toxic and preneoplastic lesions are induced. The nutritional status of the diets used in the long-term experiments was marginally deficient in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a cancer initiation/promotion model in rat liver provided important information about the possible mechanisms involved during the initial stages of cancer development by this apparently nongenotoxic mycotoxin. These studies supported the findings of long-term investigations indicating that a cytotoxic/proliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed for cancer induction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion.
Human Herpesvirus 8 DNA in Serum During Seroconversion in Allogeneic Bone Marrow Transplant Recipients
Authors: Giuseppe Gentile, Angela Capobianchi, Antonio Volpi, Giorgio Palù, Francesca Pica, Arianna Calistri, Maria Angela Biasolo, Pietro Martino
Journal: JNCI Journal of the National Cancer Institute (2005)

To determine the prevalence of human herpesvirus 8 (HHV-8) infection, the rate of HHV-8 seroconversion, and the presence of serum HHV-8 DNA after bone marrow transplantation (BMT), we evaluated sera from 187 Italian BMT donor-recipient pairs. Antibodies to lytic and latent HHV-8 antigens were detected by immunofluorescence. Sera of donor-recipient pairs who seroconverted were examined by real-time polymerase chain reaction (RT-PCR). Before BMT, 24 (13%) of 187 donors and 20 (11%) of 187 recipients were seropositive; after BMT, 28 (15%) of 187 recipients were seropositive. Seroconversion occurred in 19 (11%) of 167 recipients seronegative at baseline: 14 (9%) from 149 seronegative donors and five (28%) from 18 seropositive donors (relative risk of seroconversion with BMT from a seropositive donor = 2.96, 95% confidence interval = 1.21 to 7.25; P = .02, two-sided Fisher's exact test). One donor and two recipients who seroconverted after BMT were positive for HHV-8 by RT-PCR. No HHV-8-related complications were observed after a median follow-up of 6 years. BMT-associated HHV-8 seroconversion is relatively common in seronegative recipients from seropositive donor, but factors other than BMT may also contribute to seroconversion.
Elder abuse should have been discussed in issue on ageing
Authors: P Badrinath, S. Ramaiah
Journal: BMJ (1998)

EDITOR—The BMJ should be complimented for devoting an entire issue to healthy ageing (25 October 1997). We were, however, surprised to find that the problem of elder abuse was not discussed. Elder abuse has attracted widespread attention in recent years. 1 2 Elder abuse may be defined as psychological (verbal), financial, sexual, or violent physical abuse that …
Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease
Authors: Ulrich Beuers, Ulrich Spengler, Franz M. Zwiebel, Juergen Pauletzki, Sven Fischer, Gustav Paumgartner
Journal: Hepatology (1992)

Beneficial effects of ursodeoxycholic acid in chronic cholestatic liver diseases have been attributed to displacement of hydrophobic bile acids from the endogenous bile acid pool. To test this hypothesis, we determined pool sizes, fractional turnover rates, synthesisiinput rates and serum levels of deoxycholic acid and chenodeoxycholic acid before and 1 mo after the start of treatment with ursodeoxycholic acid (13 to 15 mg/kg body wt/day) in four healthy volunteers and five patients with chronic cholestatic liver diseases (three with primary biliary cirrhosis and two with primary sclerosing cholangitis). Bile acid kinetics were determined by combined capillary gas chromatographyisotope ratio mass spectrometry in serum samples after administration of [2H4] deoxycholic acid and [13C]chenodeoxycholic acid. In healthy volunteers, deoxycholic acid pool sizes decreased during administration of ursodeoxycholic acid by 72%. In patients with cholestatic liver diseases, deoxycholic acid pool sizes before ursodeoxycholic acid treatment were only 13% of those in healthy volunteers and were unaffected by ursodeoxycholic acid treatment. Chenodeoxycholic acid pool sizes were not different in healthy volunteers and in patients with cholestatic liver disease, and were not altered by ursodeoxycholic acid treatment. In both healthy volunteers and patients with cholestatic liver disease, synthesidinput rates and serum levels of deoxycholic acid and chenodeoxycholic acid were not altered by ursodeoxycholic acid treatment. Because in our patients improvement of serum liver tests during short-term ursodeoxycholic acid treatment was noted without a decrease of the pool sizes of the major hydrophobic bile acids, we conclude that displacement of hydrophobic endogenous bile acids is not the mechanism of action of ursodeoxycholic acid in chronic cholestatic liver disease. (Hepatology 1992; 15603-608).
Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.
Authors: H Hanke, M Oberhoff, S Hanke, S Hassenstein, J Kamenz, K M Schmid, E Betz, K R Karsch
Journal: Circulation (1992)

The proliferative response induced by balloon angioplasty is known to be an important factor in the development of restenosis after successful coronary angioplasty.To study the effects of low-molecular-weight heparin (LMWH) on cellular proliferation after experimental balloon angioplasty, LMWH (3.9 kd, 400 anti-Xa units/kg/day) was given to 20 male New Zealand White rabbits. After an intimal fibromuscular plaque was induced by electrical stimulation in the right carotid artery, LMWH was applied during the 7 days after balloon dilatation. As the control group, 20 other rabbits underwent balloon angioplasty without application of LMWH. The vessels were excised 3, 7, 14, and 28 days after balloon treatment. During the final 18 hours before the rabbits were killed, bromodeoxyuridine was applied. Intimal wall thickness increased from 13 +/- 5 cell layers (preangioplasty control group) to 20 +/- 6 cell layers in the LMWH-treated group at 28 days (p less than 0.05). In contrast, histological examination of control animals 28 days after angioplasty revealed a significant increase to 35 +/- 15 cell layers (p less than 0.01). Immunohistological quantification showed a significant increase (p less than 0.001) of cells undergoing DNA synthesis at 3 (10.2 +/- 4.2%) and 7 (7.7 +/- 4.8%) days after balloon dilatation in control animals. In contrast, at 3 and 7 days after balloon treatment, the percentage of cells undergoing DNA synthesis in LMWH-treated rabbits was lower (3 days, 2.7 +/- 1.8%; 7 days, 1.9 +/- 0.3%) than the corresponding untreated controls but showed a significant increase (p less than 0.01) compared with the preangioplasty controls. The differences between the two groups were statistically significant, however (3 days, p less than 0.01; 7 days, p less than 0.05). As early as 14 days after angioplasty, the extent of cellular proliferation was normalized and was comparable to the preintervention levels in both groups.Our data indicate that the proliferative response after balloon angioplasty can be reduced in vivo by early treatment with LMWH and thus encourage further clinical investigations.
Metastatic Inflammatory Myofibroblastic Tumor Imaged by PET/CT
Authors: Phillip H. Kuo, Stacy Spooner, Parminder Deol, Travis Monchamp
Journal: Clinical Nuclear Medicine (2006)

We describe a case using PET/CT to image a metastatic inflammatory myofibroblastic tumor (IMT). IMTs are a collection of uncommon tumors that contain myofibroblasts and inflammatory cells, as the name suggests. Before the PET/CT scan, the patient had a left pneumonectomy and a partial resection of the occipital lobe for IMTs. The PET/CT scan with FDG demonstrated foci of intense activity in the proximal jejunum and body of the pancreas. Disease above the diaphragm still persisted as supraclavicular adenopathy. The scan showed no evidence for local recurrence in the brain or left hemithorax.
Energy conversion efficiency in human left ventricle.
Authors: T Kameyama, H Asanoi, S Ishizaka, K Yamanishi, M Fujita, S Sasayama
Journal: Circulation (1992)

Left ventricular mechanical efficiency is one of the most important measures of left ventricular pump performance. Several clinical studies, however, have shown that mechanical efficiency does not fall substantially as the heart fails. To clarify the insensitivity of mechanical efficiency to the change in pump performance, we analyzed human left ventricular mechanical efficiency, applying the concept of left ventricular systolic pressure-volume area (PVA).PVA correlates linearly with myocardial oxygen consumption per beat (MVO2): MVO2 = a.PVA+b, and represents the total mechanical energy of contraction. We determined MVO2-PVA relation and external work in 11 patients with different contractile states. We also calculated the energy transfer from MVO2 to PVA (PVA/MVO2 efficiency), that from PVA to external work (work efficiency), and mechanical efficiency (external work/MVO2). Left ventricular pressure-volume loops were constructed by plotting the instantaneous left ventricular pressure against the left ventricular volume at baseline and during pressure loading. The contractile properties of the ventricle were defined by the slope of the end-systolic pressure-volume relation (Ees). Pressure elevation raised external work by 41.4%, PVA by 71.2%, and MVO2 by 54.5%. These changes were associated with a decrease in work efficiency and an increase in PVA/MVO2 efficiency. The opposite directional changes in these two efficiencies rendered the mechanical efficiency constant. The slope, a, of the relation between MVO2 and PVA was relatively constant (2.46 +/- 0.33) over the range of 0.8-8.8 mm Hg/ml of Ees, but the oxygen axis intercept, b, tended to decrease with the reduction in Ees. PVA/MVO2 efficiency correlated inversely (r = -0.66, p less than 0.05) with Ees, whereas work efficiency correlated linearly with Ees (r = 0.91, p less than 0.01).Mechanical efficiency is not appreciably affected by changes in loading and inotropic conditions as long as the left ventricular contractility is not severely depressed.
Glucose-Insulin-Potassium for Suspected Acute Myocardial Infarction—Reply
Authors: Harry P. Selker, James E. Udelson, Joni R. Beshansky
Journal: JAMA (2012)

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Cellular endotoxin desensitization in patients with severe chronic heart failure
Authors: Rakesh Sharma, Aidan P. Bolger, Mathias Rauchhaus, Stephan von Haehling, Wolfram Doehner, Ian M. Adcock, Peter J. Barnes, Philip A. Poole‐Wilson, Hans‐Dieter Volk, Andrew J.S. Coats, Sam Lim, Stefan D. Anker
Journal: European Journal of Heart Failure (2005)
Characterization of acetylcholine-induced membrane hyperpolarization in endothelial cells.
Authors: G F Chen, D W Cheung
Journal: Circulation Research (1992)

The characteristics of the hyperpolarization response to acetylcholine (ACh) in endothelial cells from the guinea pig coronary artery were studied by microelectrode recording technique. ACh (30 nM to 3 microM) induced membrane hyperpolarization in a dose-dependent manner. The sustenance of the response required the presence of external calcium. The hyperpolarization was not affected by nifedipine (1 microM) but was inhibited by the potassium channel blockers charybdotoxin (10 nM), tetraethylammonium (1 mM), and 4-aminopyridine (0.5 mM). Glibenclamide (10 microM) and apamin (1 microM) were not effective. The inhibitors of endothelium-derived relaxing factor/nitric oxide synthesis N omega-nitro L-arginine (50 microM) and NG-monomethyl L-arginine (30 microM) had no effect on the resting membrane potential or the ACh-induced responses. No hyperpolarization was observed with application of sodium nitroprusside (10 microM) or 8-bromo-cGMP (0.1 microM). Ouabain (10 microM) depolarized the membrane significantly by 5 mV, but the ACh hyperpolarization was not affected. Indomethacin (10 microM) was without effect on the resting membrane potential or the hyperpolarization to ACh. These results show that ACh-induced hyperpolarization is dependent on external calcium and can be inhibited by certain potassium channel blockers. The hyperpolarization response is not mediated by endothelium-derived relaxing factor/nitric oxide, cGMP, a cyclooxygenase product, or stimulation of the Na-K pump.
Palliative care is not same as end of life care
Authors: C. M. Reid, J. Gibbins, R. McCoubrie, K. Forbes
Journal: BMJ (2011)

Gott and colleagues’ paper resonates with our research findings from focus groups with ward staff caring for dying patients.1 2

We wonder if terminology is a barrier that was not discussed. The provision of palliative care should depend on need not prognosis.3 However, focus group participants considered palliative care as …
Effect of Clinical Decision-Support Systems
Authors: Tiffani J. Bright, Anthony Wong, Ravi Dhurjati, Erin Bristow, Lori Bastian, Remy R. Coeytaux, Gregory Samsa, Vic Hasselblad, John W. Williams, Michael D. Musty, Liz Wing, Amy S. Kendrick, Gillian D. Sanders, David Lobach
Journal: Annals of Internal Medicine (2012)

Background: Despite increasing emphasis on the role of clinical decision-support systems (CDSSs) for improving care and reducing costs, evidence to support widespread use is lacking. Purpose: To evaluate the effect of CDSSs on clinical outcomes, health care processes, workload and efficiency, patient satisfaction, cost, and provider use and implementation. Data Sources: MEDLINE, CINAHL, PsycINFO, and Web of Science through January 2011. Study Selection: Investigators independently screened reports to identify randomized trials published in English of electronic CDSSs that were implemented in clinical settings; used by providers to aid decision making at the point of care; and reported clinical, health care process, workload, relationship-centered, economic, or provider use outcomes. Data Extraction: Investigators extracted data about study design, participant characteristics, interventions, outcomes, and quality. Data Synthesis: 148 randomized, controlled trials were included. A total of 128 (86%) assessed health care process measures, 29 (20%) assessed clinical outcomes, and 22 (15%) measured costs. Both commercially and locally developed CDSSs improved health care process measures related to performing preventive services (n = 25; odds ratio [OR], 1.42 [95% CI, 1.27 to 1.58]), ordering clinical studies (n = 20; OR, 1.72 [CI, 1.47 to 2.00]), and prescribing therapies (n = 46; OR, 1.57 [CI, 1.35 to 1.82]). Few studies measured potential unintended consequences or adverse effects. Limitations: Studies were heterogeneous in interventions, populations, settings, and outcomes. Publication bias and selective reporting cannot be excluded. Conclusion: Both commercially and locally developed CDSSs are effective at improving health care process measures across diverse settings, but evidence for clinical, economic, workload, and efficiency outcomes remains sparse. This review expands knowledge in the field by demonstrating the benefits of CDSSs outside of experienced academic centers. Primary Funding Source: Agency for Healthcare Research and Quality.