Reducing the hypoxic fraction of a tumour model by growth in low glucose.

The question of whether growth under low glucose conditions leads to a reduced amount of cell hypoxia was investigated using an in vitro tumour analogue, the sandwich system. In this multicellular system, the interplay between diffusion and consumption of oxygen and nutrients results in spatial gradients of these environmental factors. Gradients in the environment lead to biological heterogeneity within the cell population. A necrotic centre, surrounded by a viable cell border, subsequently develops. Cells adjacent to the necrotic centre in sandwiches are hypoxic and are in an environment somewhat analogous to that of cells adjacent to necrotic regions in solid tumours. Using sandwiches of the 9L and V79 cell lines, the effects of growth under low glucose conditions on the degree of hypoxia in regions adjacent to the necrotic centre were investigated. Per-cell binding of 3H-misonidazole, assessed by autoradiography, was used as an indicator of oxygen deprivation. It was found that the extent of the hypoxic region and the severity of hypoxia were considerably reduced by growing sandwiches in a glucose concentration of 0.6 mM rather than 6.5 mM. This reduction was found in conjunction with a smaller viable border; it occurred despite the fact that the average per-cell oxygen consumption is higher in the low glucose sandwiches. The data are qualitatively consistent with a joint oxygen-glucose deprivation model for cell necrosis

Dorsal and ventral stimuli in cell–material interactions: effect on cell morphology

Cells behave differently between bidimensional (2D) and tridimensional (3D) environments. While most of the in vitro cultures are 2D, most of the in vivo extracellular matrices are 3D, which encourages the development of more relevant culture conditions, seeking to provide more physiological models for biomedicine (e.g., cancer, drug discovery and tissue engineering) and further insights into any dimension-dependent biological mechanism. In this study, cells were cultured between two protein coated surfaces (sandwich-like culture). Cells used both dorsal and ventral receptors to adhere and spread, undergoing morphological changes with respect to the 2D control. Combinations of fibronectin and bovine serum albumin on the dorsal and ventral sides led to different cell morphologies, which were quantified from bright field images by calculating the spreading area and circularity. Although the mechanism underlying these differences remains to be clarified, excitation of dorsal receptors by anchorage to extracellular proteins plays a key role on cell behavior. This approach—sandwich-like culture—becomes therefore a versatile method to study cell adhesion in well-defined conditions in a quasi 3D environment

Late diagnosis of abdominal aortic aneurysms substantiates underutilization of abdominal aortic aneurysm screening for Medicare beneficiaries

ObjectiveAbdominal aortic aneurysm (AAA) screening remains largely underutilized in the U.S., and it is likely that the proportion of patients with aneurysms requiring prompt treatment is much higher compared with well-screened populations. The goals of this study were to determine the proportion of AAAs that required prompt repair after diagnostic abdominal imaging for U.S. Medicare beneficiaries and to identify patient and hospital factors contributing to early vs late diagnosis of AAA.MethodsData were extracted from Medicare claims records for patients at least 65 years old with complete coverage for 2 years who underwent intact AAA repair from 2006 to 2009. Preoperative ultrasound and computed tomography was tabulated from 2002 to repair. We defined early diagnosis of AAA as a patient with a time interval of greater than 6 months between the first imaging examination and the index procedure, and late diagnosis as patients who underwent the index procedure within 6 months of the first imaging examination.ResultsOf 17,626 patients who underwent AAA repair, 14,948 met inclusion criteria. Mean age was 77.5 ± 6.1 years. Early diagnosis was identified for 60.6% of patients receiving AAA repair, whereas 39.4% were repaired after a late diagnosis. Early diagnosis rates increased from 2006 to 2009 (59.8% to 63.4%; P < .0001) and were more common for intact repair compared with repair after rupture (62.9% vs 35.1%; P < .0001) and for women compared with men (66.3% vs 59.0%; P < .0001). On multivariate analysis, repair of intact vs ruptured AAAs (odds ratio, 3.1; 95% confidence interval, 2.7-3.6) and female sex (odds ratio, 1.4; 95% confidence interval, 1.3-1.5) remained the strongest predictors of surveillance. Although intact repairs were more likely to be diagnosed early, over one-third of patients undergoing repair for ruptured AAAs received diagnostic abdominal imaging greater than 6 months prior to surgery.ConclusionsDespite advances in screening practices, significant missed opportunities remain in the U.S. Medicare population for improving AAA care. It remains common for AAAs to be diagnosed when they are already at risk for rupture. In addition, a significant proportion of patients with early imaging rupture prior to repair. Our findings suggest that improved mechanisms for observational management are needed to ensure optimal preoperative care for patients with AAAs

Impact of proton pump inhibitor treatment on gastrointestinal bleeding associated with non-steroidal anti-inflammatory drug use among post-myocardial infarction patients taking antithrombotics: nationwide study

Study question What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)? Methods This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models. Study answer and limitations The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82 955 post-myocardial infarction patients (mean age 67.4 years, 64% (n=53 070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35 233) filled at least one prescription for NSAIDs and 45.5% (n=37 771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding. What this study adds In post-myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. Funding, competing interests, data sharing AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation

Importance of clinical measures of ischemia in the prognosis of patients with documented coronary artery disease

AbstractTo examine the value of clinical measures of ischemia for stratifying prognosis, 5,886 consecutive patients who had symptomatic significant (≥75% stenosis) coronary artery disease were studied. Using the Cox regression model in a randomly selected half of the patients, the prognostically independent clinical variables were weighted and arranged into a simple angina score: angina score = angina course × (1 + daily angina frequency) + ST-T changes, where angina course was equal to 3 if unstable or variant angina was present, 2 if the patient's angina was progressive with nocturnal episodes, 1 if it was progressive without nocturnal symptoms and 0 if it was stable; 6 points were added for the presence of “ischemic” ST-T changes. This angina score was then validated in an independent patient sample.The score was a more powerful predictor of prognosis than was any individual anginal descriptor. Furthermore, the angina score added significant independent prognostic information to the patient's age, sex, coronary anatomy and left ventricular function. Patients with three vessel disease and a normal ventricle (n = 1,233) had a 2 year infarction-free survival rate of 90% with an angina score of 0 and a 68% survival rate with an angina score ≥9. With an ejection fraction <50% and three vessel disease (n = 1,116), the corresponding infarction-free survival figures were 76 and 56%. Thus, a careful summarization of clinical markers of ischemia in the form of an angina score can provide a powerful prognostic tool and may aid clinicians in identifying high risk patients who are candidates for aggressive therapeutic interventions

Clinical judgement and therapeutic decision making

AbstractClinical decision making is under increased scrutiny due to concerns about the cost and quality of medical care. Variability in physician decision making is common, in part because of deficiencies in the knowledge base, but also due to the difference in physicians' approaches to clinical problem solving. Evaluation of patient prognosis is a critical factor in the selection of therapy, and careful attention to methodology is essential to provide reliable information.Randomized controlled clinical trials provide the most solid basis for the establishment of broad therapeutic principles. Because randomized studies cannot be performed to address every question, observational studies will continue to play a complementary role in the evaluation of therapy. Randomized studies in progress, meta analyses of existing data, and increased use of administrative and collaborative clinical data bases will improve the knowledge base for decision making in the future

Race and Ethnicity, Obesity, Metabolic Health, and Risk of Cardiovascular Disease in Postmenopausal Women

Background It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups. Methods and Results We identified 14 364 postmenopausal women from the Women\u27s Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m2) as normal weight (body mass index 18.5 to P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with only 2 metabolic abnormalities, cardiovascular risk was increased in black women who were overweight (HR 1.77) or obese (HR 2.17) but not in white women who were overweight (HR 0.98) or obese (HR 1.06). Overweight and obese women with ≤1 metabolic abnormality did not have increased cardiovascular risk, regardless of race or ethnicity. Conclusions Metabolic abnormalities appeared to convey more cardiovascular risk among black women

Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLR1) with CAD

Abstract Background The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study. Methods ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD. Results In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study. Conclusion Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.http://deepblue.lib.umich.edu/bitstream/2027.42/112726/1/12881_2008_Article_317.pd