tbuckley/cabot-search huggingface dataset:
Lesson of the week: Doxycycline induced intracranial hypertension
Authors: J Lochhead
Journal: BMJ (2003)

<h3>Background</h3> Diabetes among older people is becoming more common worldwide. Polypharmacy is an important issue among older people with multimorbidity; however, relevant studies focusing on older people with diabetes are scarce. Therefore, the role of polypharmacy in this vulnerable population remains uncertain. The aim of this study is to investigate the prevalence of polypharmacy among older people with and without diabetes, and to determine the potential risk factors for polypharmacy. <h3>Methods</h3> A nationally representative cross-sectional study, ELSA 2012/2013, was used and 7729 participants aged 50–109 were investigated. Polypharmacy was defined as taking five to nine long-term used medications daily for chronic diseases or chronic symptoms, while using ten or more medications was categorised as excessive polypharmacy. The presence of illness was defined as either self-reported diagnosis or being prescribed specific medications for the condition. The number of comorbidities was generated based on the combined diagnoses excluding diabetes. Multinomial logistic regression was applied to estimate risk factors for polypharmacy, and potential social determinants were also included. <h3>Results</h3> The prevalence of polypharmacy was 21.4% in 2012, and only 3% was excessive polypharmacy. 51.6% of people with type 2 diabetes reported polypharmacy and 10.2% excessive polypharmacy. These rates were significantly higher than the 16.4% polypharmacy and 1.8% excessive polypharmacy among people without diabetes (p&lt;0.001). 74.6% diabetic people had three or more comorbidities, compared with 40.8% in people without diabetes (p&lt;0.001). Among people with three or more comorbidities, polypharmacy was present in 61.5% of people with diabetes, compared with 36.0% in people without diabetes. Significant risk factors for polypharmacy were diabetes (Relative-risk ratios/RRR=4.06, 95% CI 3.38, 4.86), older age (RRR=1.02, 95% CI 1.01, 1.03), male (RRR=0.64, 95% CI 0.55, 0.75), more comorbidity (RRR=2.46, 95% CI 2.30, 2.62), living with a partner (RRR=1.20, 95% CI 1.01, 1.42), and less wealth (RRR=0.93, 95% CI 0.87, 0.98). However, age, living with partner, and wealth were not significantly related to excessive polypharmacy. Diabetes and the number of comorbidities were predominant risk factors for excessive polypharmacy. <h3>Conclusion</h3> Polypharmacy was a prevalent phenomenon in the English older population, and it was more severe in people with diabetes. The presence of diabetes and having comorbidities were the main contributors to polypharmacy and excessive polypharmacy after adjusting for important covariates. Current evidences confirm both health condition and socioeconomic status are associated with medication use. This research is currently ongoing, and more factors will be studied in the future.
Abstract 13163: Ultrastructural Features of Ischemic Tissue Following Application of a Bio-membrane Based Progenitor Cardiomyocyte Patch for Myocardial Infarction Repair
Authors: Dehua Chang, Wenfeng Cai, Christian Paul, Teruo Okano, Ronald Millard, Yigang Wang
Journal: Circulation (2014)

Background and Objective:  Implantation of cell-sheets into damaged regions of the heart after myocardial infarction (MI) has been shown to improve heart function. We report here the potential role of applying a bio-membrane ‘cell patch’ created of cured fetal bovine serum and fetal mouse fibroblasts as a substrate for iPSC-derived precursor CM in a mouse MI model created by ligation of the left anterior descending (LAD) artery.   Methods and Results:  iPSC derived progenitor cells were transduced using plv-IRES-ZsGreen (GFP)-firefly luciferase lentivirus vectors with a cardiac-specific Na + -Ca 2+  exchange (NCX1) promoter in order to convey cardiogenic differentiation potential. iPSC-CM sheets were created on a substrate of cured albumin and fetal fibroblasts in thermo-responsive dishes and transplanted over the transmural myocardial infarction (MI) region in a mouse model. Mice were divided into four groups, 1) Sham; 2) MI; 3) MI + iPSC without NCX1 treated cells (MI+iPSC Null ) and 4) MI + iPSC receiving NCX1 promoter treated cells (MI+iPSC NCX1) . Echocardiography was performed 4 weeks after cell patch application, followed by histological and transmission electron microscopy (TEM) analysis (Fig. 1). More than 99% sarcomere alpha-actinin positive cells were obtained by group 4. Four weeks after cell patch application, large numbers of transplanted CMs were observed in the infarct region with significant improvements in left ventricular performance and remodeling in mice from group 4 as compared with group 3. No teratoma formation was detected in any of the treatment groups.   Conclusion:  Manipulation of iPSC using viral vectors encoding markers under the control of NCX1 promoter yields large numbers of iPSC-CM with associated favorable morphological and ultrastructural tissue changes. These changes resulted in infarct size reduction and restoration of cardiac function after MI.
Scrips for Viagra to be free in Ireland
Authors: Doug Payne
Journal: BMJ (1999)

Ireland is about to become one of the few European countries where sildenafil citrate (Viagra) is free under its health service. The minister for health, Brian Cowen, followed advice from an expert panel set up to monitor the prescribing trends and safety of the drug and announced on 20 May that the drug will be available free under the general medical scheme for all patients with medical cards from 1 July.

Other patients will be able to claim back its cost under certain circumstances. …
The cohesin complex: sequence homologies, interaction networks and shared motifs
Authors: Susan Jones, John Sgouros
Journal: Genome biology (2001)

Cohesin is a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis. The links are formed during DNA replication and destroyed during the metaphase-to-anaphase transition. In budding yeast, the 14S cohesin complex comprises at least two classes of SMC (structural maintenance of chromosomes) proteins - Smc1 and Smc3 - and two SCC (sister-chromatid cohesion) proteins - Scc1 and Scc3. The exact function of these proteins is unknown.Searches of protein sequence databases have revealed new homologs of cohesin proteins. In mouse, Mmip1 (Mad member interacting protein 1) and Smc3 share 99% sequence identity and are products of the same gene. A phylogenetic tree of SMC homologs reveals five families: Smc1, Smc2, Smc3, Smc4 and an ancestral family that includes the sequences from the Archaea and Eubacteria. This ancestral family also includes sequences from eukaryotes. A cohesion interaction network, comprising 17 proteins, has been constructed using two proteomic databases. Genes encoding six proteins in the cohesion network share a common upstream region that includes the MluI cell-cycle box (MCB) element. Pairs of the proteins in this network share common sequence motifs that could represent common structural features such as binding sites. Scc2 shares a motif with Chk1 (kinase checkpoint protein), that comprises part of the serine/threonine protein kinase motif, including the active-site residue.We have combined genomic and proteomic data into a comprehensive network of information to reach a better understanding of the function of the cohesin complex. We have identified new SMC homologs, created a new SMC phylogeny and identified shared DNA and protein motifs. The potential for Scc2 to function as a kinase - a hypothesis that needs to be verified experimentally - could provide further evidence for the regulation of sister-chromatid cohesion by phosphorylation mechanisms, which are currently poorly understood.
Patients with newly diagnosed multiple myeloma and chromosome 1 amplification have poor outcomes despite the use of novel triplet regimens
Authors: Noa Biran, Jyoti Malhotra, Emilia Bagiella, Hearn Jay Cho, Sundar Jagannath, Ajai Chari
Journal: American Journal of Hematology (2014)

The prognostic impact of amplification of chromosome 1(C1A) in newly diagnosed multiple myeloma (nMM) patients treated with the most commonly used bortezomib-based triplet regimens is unclear. In this study, we analyzed the outcome of novel triplet therapies in a series of unselected patients with C1A detected by FISH. We identified 28 unselected nMM patients with C1A who had a gain of 1q21 locus. Despite 50% of patients being diagnosed at ISS stage 1 or 2 and 93% having no other high-risk molecular findings, the median overall survival of all patients was only 37 months, with 8 deaths (29%) occurring 8-37 months after diagnosis. Those who died had a median of four lines (range was 1-8) of therapy. Moreover, 71% of patients were non-Caucasian. Extra-osseous and CNS involvement occurred in 36 and 11% of patients respectively. Gain of the long arm of chromosome 1 detected by FISH remains a high-risk prognostic marker even in the setting of novel triplet therapies.
Health and Environmental Impacts of Increased Generation of Coal Ash and FGD Sludges: Report to the Committee on Health and Ecological Effects of Increased Coal Utilization
Authors: Chakra J. Santhanam, Richard R. Lunt, Sandra L. Johnson, Charles B. Cooper, Philip S. Thayer, Julian W. Jones
Journal: Environmental Health Perspectives (1979)

Incremental environmental impacts of coal ash and flue gas desulfurization sludge disposal associated with the increased use of coal for generation are surveyed. These wastes are currently disposed of exclusively on land. Major potential impacts of land disposal are surface water contamination and land degradation. Air quality impacts in the form of dust from coal ash disposal sites are also considered. Disruption of regional hydrology and reduction of soil productivity can result in a loss of vegetation. (2 maps, 6references, 20 tables)
A paper that changed my practice: From paper to practice doesn't always take a decade
Authors: G. Warner
Journal: BMJ (2002)

It's not often that a paper changes practice before it is published. It happened to m,however, and, as its a paper that's only recently been published, 1 2I wait to see whether it will change many other general practitioners'practice too.

Paul Little and colleagues' study published on 3 August 2002 on the different methods of measuring blood pressure in general practice was carried out in my practice (though I was not involved). Having tried wearing an ambulatory blood pressure monitor for 24 hours some years ago, I knew …
The Commonality of Risk Factors for Nosocomial Colonization and Infection with Antimicrobial-Resistant <i>Staphylococcus aureus</i>, <i>Enterococcus</i>, Gram-Negative Bacilli, <i>Clostridium difficile</i>, and <i>Candida</i>
Authors: Nasia Safdar, Dennis G. Maki
Journal: Annals of Internal Medicine (2002)

Recent years have witnessed a rapidly growing crisis in antimicrobial resistance, especially among microorganisms that cause nosocomial infection. To better understand common risk factors among multiresistant organisms, this review explores risk factors for nosocomial infection with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, Clostridium difficile, extended-spectrum β-lactamase-producing gram-negative bacilli, and Candida. This review comprises data from 74 published studies; 53 (71%) were retrospective studies and addressed few risk factors or did not quantify risk. The analysis shows impressive commonality of risk factors across these diverse multiresistant organisms: advanced age; underlying diseases and severity of illness; inter-institutional transfer of the patient, especially from a nursing home; prolonged hospitalization; gastrointestinal surgery or transplantation; exposure to invasive devices of all types, especially central venous catheters; and exposure to antimicrobial drugs, especially cephalosporins. More restricted use of antibiotics, especially cephalosporins, and strategies to prevent medical device-related infection and cross-infection in the hospital would yield benefit with all types of resistant organisms. Preemptive isolation of all patients with risk factors for infection by resistant organisms would very likely reduce secondary spread within the hospital. Conversely, programs that focus on only one organism or one antimicrobial drug are unlikely to succeed. Prospective studies of sufficient size that address all potential risk factors, especially individual anti-infective agents, and that use matched controls who are shown by surveillance cultures to be free of colonization by resistant organisms would enhance understanding of the epidemiology of antimicrobial resistance in institutions and guide efforts to develop more effective strategies for prevention.
Dose dependent inhibition of uridine phosphorylase (UP) by eniluracil (EU): Was the clinical inferiority of the EU/5-fluorouracil (5-FU) phase III trials due to an unrecognized inhibition of 5-FU anabolism?
Authors: J. Fourie, V. Guarcello, R. B. Diasio
Journal: Journal of Clinical Oncology (2006)

2058 Background: Eniluracil (EU) is an irreversible inactivator of dihydropyrimidine dehydrogenase (DPD). EU inhibits DPD dependent 5-fluorouracil (5-FU) catabolism, allowing for oral 5-FU administration with essentially complete bioavailability. Although earlier murine studies suggested an increased antitumor effect when EU was administered before 5-FU, clinical studies used co-administered EU and 5-FU (ratio: 10 EU:1 5-FU) (b.i.d.). These phase III trials demonstrated inferiority compared to a regimen of 5-FU/leukovorin, leading to discontinuation of EU development. We hypothesize that the clinical failure of this EU/5-FU schedule may have resulted from competitive inhibition of 5-FU anabolic (ANA) activation by EU. In this study we examined whether EU could competitively inhibit uridine phosphorylase (UP) or orotate phosphoribosyl transferase (OPRT), the primary ANA enzymes of 5-FU. Methods: The cytoplasmic fraction of human embryonic kidney cells (HEK-293) was used as the source of UP and OPRT. Reverse phase HPLC with radioactivity detection was used to quantify [2- 14 C]-uracil formation from [2- 14 C]-uridine (UP activity) and to quantify [6- 14 C]-FUMP formation from [6- 14 C]-5-FU (OPRT activity). For UP activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 150 μM [2- 14 C]-uridine. For OPRT activity, reaction mixtures consisted of increasing concentrations of EU in phosphate buffer containing 5 μM [6- 14 C]-FU and 100 μM benzylacyclouridine (UP inhibitor). Reactions were initiated with addition of UP/OPRT enzyme source and allowed to proceed for 30 min at 37°C. Results: EU displayed dose-dependent competitive inhibition of UP activity (IC 50 = 0.375 mM). In particular, the EU/5-FU ratio of 2.5:1 produced approximately 50% inhibition of UP activity. In contrast, EU did not inhibit OPRT activity. Conclusions: This study demonstrates that EU competitively inhibits UP, an important enzyme in 5-FU ANA activation, and suggests that changing the dose ratio and/or increasing the interval between EU and 5-FU administration may be useful in optimizing 5-FU antitumor efficacy. [Table: see text]
Abstract 366: Translational modeling of docetaxel-thalidomide combination treatment in metastatic, castrate-resistant prostate cancer: predicting clinical response using preclinical data
Authors: Eric Fernandez, Hitesh Mistry, Frances Brightman, David Orrell, William L. Dahut, William D. Figg, Wilfried D. Stein, Christophe Chassagnole
Journal: Cancer Research (2014)

Abstract A major cause of drug failure in the clinic is that preclinical studies do not predict with sufficient certainty what will happen in clinical practice. Accurately translating information from animal studies to the clinic would have a major impact on attrition rate. We have developed a mathematical model of a tumor cell population called the Virtual Tumour, which has been used extensively to predict the efficacy of single drug or drug combination treatment in preclinical studies. We have now extended and adapted our preclinical model to predict efficacy in the clinic, thus creating the “Virtual Tumour Clinical.” Here we show a comparative study of the preclinical Virtual Tumour calibrated model for prostate tumor xenografts in mice, with a Virtual Tumour Clinical version calibrated with a clinical data set comprising 53 prostate cancer patients treated with thalidomide, 25 treated with docetaxel and 50 treated with a docetaxel and thalidomide combination. PSA measurements were used as proxy for tumor size. We analysed the consistency, the capability and the limitations of the models in translating the effect of the drug combination from the preclinical situation to the clinic. Citation Format: Eric Fernandez, Hitesh Mistry, Frances Brightman, David Orrell, William L. Dahut, William D. Figg, Wilfried D. Stein, Christophe Chassagnole. Translational modeling of docetaxel-thalidomide combination treatment in metastatic, castrate-resistant prostate cancer: predicting clinical response using preclinical data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2014-366
Abstract 19134: Elevated Troponin T is Associated with Adverse Outcomes After Aortic Valve Replacement
Authors: Ashwat Dhillon, Kanhaiya Poddar, Murat Tuzcu, Eric Roselli, Lars Svensson, Samir Kapadia
Journal: Circulation (2014)

Background: Data regarding association of elevated cardiac enzymes and adverse outcomes in patients who undergo aortic valve replacement (AVR) has been inconclusive. Role of coronary revascularization prior to AVR remains uncertain. We sought to understand prognostic implication of post procedure troponin T (TnT) elevation in patients undergoing AVR. Hypothesis: We hypothesized that patients with significantly elevated TnT after AVR will have worse outcomes representing important coronary circulation which is not revascularized. Methods: We retrospectively studied 4648 consecutive patients who underwent AVR at a single tertiary care center between January 2007 and December 2013. These were divided into surgical AVR (SAVR) and transcatheter AVR (TAVR). Median post procedure peak TnT was identified in the SAVR and TAVR groups. Patients were divided into quartiles based on median TnT level. Results: Of 4648 patients who underwent AVR, 4200 (66% male) were SAVR and 448 (59% male) were TAVR. Median post procedure peak TnT values in the TAVR and SAVR group were 0.19 [0.08-0.39] &amp; 0.36 [0.22-0.64] respectively (p&lt;0.001). 6 month mortality was 1.5% (65/4200) in SAVR cases and 2.7% (12/448) in TAVR cases (p=0.08). In patients with TnT less than 50 th percentile, 6 month mortality was 0.7% &amp; 1.8% after SAVR &amp; TAVR respectively (p=0.1). In patients with TnT higher than 50 th percentile, 6 month mortality was 2.4% &amp; 3.6% after SAVR &amp; TAVR respectively (p=0.26). In the SAVR group, mortality was 0.7% in patients with TnT levels less than 50 th percentile &amp; 2.4% in patients with TnT higher than 50 th percentile (p&lt;0.001). See Figure. Conclusion: Peak troponin T was significantly higher after SAVR as compared to TAVR. Higher post procedure peak TnT is associated with increased 6 month mortality. These results are highly significant in the SAVR group. The mechanism and significance of these findings requires further studies.
Abstract 9393: Prognostic Value of Cardiac Sympathetic Imaging with Metaiodobenzylguanidine for the Prediction of Mortality in Patients with Cardiorenal Syndrome
Authors: Hidemichi Kouzu, Takahiro Doi, Mina Kawamukai, Junichi Nishida, Atsushi Mochizuki, Atsuko Muranaka, Nobuaki Kokubu, Shinya Shimoshige, Satoshi Yuda, Mamoru Hase, Akiyoshi Hashimoto, Tomoaki Nakata, Kazufumi Tsuchihashi, Tetsuji Miura
Journal: Circulation (2011)

Background: Augmentation of sympathetic nerve activity (SNA) is one of the underlying pathphysiologies of cardiorenal syndrome (CRS). However, impact of augmented SNA on prognosis in CRS remains unknown. Objective: We examined whether change in cardiac SNA detectable by metaiodobenzylguanidine (MIBG) imaging predicts mortality in patients with CRS. Methods and Results: Cardiac SNA activity was quantified as heart-to-mediastinum ratio (HMR) of MIBG image in 280 patients (aged 61 ± 16 years, 73% male) with heart failure (26% ischemic etiology) and reduced left ventricular ejection fraction (&lt;50%). Patients with end-stage renal disease were excluded, and those with estimated glomerular filtration rate of &lt;60 ml/min/1.73m 2 were defined as patients with CRS. During 50 ± 35 months of follow-up, cardiac death occurred in 48 patients (83% heart failure, 17% sudden death). Compared with 113 non-CRS patients, 167 CRS patients were older and had higher prevalence of diabetes, lower ejection fraction, lower hemoglobin level and worse 5-year survival rate (87.4% vs. 75.6% p&lt;0.01). In a Cox proportional hazards model, late HMR of &lt;1.57 (hazard ratio for mortality (HR): 6.98; 95% confidence interval (CI) = 3.33-16.52; p&lt;0.01) and 1 mg/dl decrease in hemoglobin level (HR: 1.29; 95% CI =1.08-1.53; p&lt;0.01) had significant predictive values, though CRS alone did not (HR: 1.57; 95% CI=0.81-3.25; p=0.18). Prognosis of CRS patients with late HMR of ≥1.57 was comparable to that of non-CRS patients (Figure 1). In CRS patients with late HMR of &lt;1.57, angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (HR: 0.29; 95% CI=0.12-0.67; p&lt;0.01) and β−blocker (HR: 0.38; 95% CI=0.17-0.82; p=0.01) were associated with better prognosis (Figure 2). Conclusions: Assessment of cardiac SNA by MIBG activity can identify high-risk patients among CRS patients. Current ACEI/ARB and β-blocker therapies appear to improve prognosis of those high-risk patients as well.