Young America: The Transformation of Nationalism before the Civil War

Mark Power Smith examines how mid-nineteenth-century European liberal nationalist movements affected United States’ nationalism(s), especially as configured by the Young America bloc of the Democratic Party. Smith finds that Europeans\u27 embrace of \u27more interventionist forms of liberalism,\u27 such as socialism, or abolitionism, \u27made popular resistance to interventionism a conservative, rather than radical force.\u2

Cobalt cardiotoxicity - effects on the contractile and non-contractile cells of the heart

Exposure to cobalt is known to cause cardiotoxicity and a common source of cobalt exposure is from metal-on-metal bearings used in prosthetic joint replacements. Acute and chronic effects of cobalt at a cellular level in the heart are not well understood. This study investigated the effects of cobalt (CoCl2) treatment on contractile and non-contractile cells of the heart. We have used isolated adult rat ventricular papillary muscles to investigate the effects of CoCl2 on basal and isoprenaline-stimulated contractile responses. In addition, we used freshly isolated primary adult rat ventricular fibroblasts maintained in short-term culture to assess the effects of CoCl2 on cell viability and proliferation. Stimulation of isolated ventricular papillary muscles with the positive inotrope isoprenaline (1uM) resulted in a consistent increase (~35% increase) over the basal contractile response as expected. Following treatment with CoCl2 (1uM) for 4h, there was a dramatic reduction in both the basal and isoprenaline-stimulated contractile responses (both~40% reduction). This effect was not due to a time-dependent decrease in contractility since in separate parallel control preparations consistent increases in contraction were observed following 1uM isoprenaline challenges at time zero and after 4h without CoCl2. Examination of the effects of CoCl2 on cardiac fibroblast proliferation and viability was performed using a range of assays. To assess effects on proliferation, MTT, neutral red and crystal violet assays were all used to compare effects of increasing concentrations of CoCl2 on the Swiss 3T3 fibroblast cell line and primary cardiac fibroblasts. Over 72h, increasing CoCl2 concentrations (up to 500uM) resulted in decreased proliferation. The MTT and Crystal violet assays showed the most reproducible results with IC50 values for CoCl2 in the range of ~300uM. Interestingly, further experiments using BrdU incorporation to assess proliferation suggested that cardiac fibroblasts were more sensitive to CoCl2 treatment than Swiss 3T3s. In the former, after either 48h or 72h there was ~80% reduction in proliferation with 25uM CoCl2 and almost no proliferation following 100–150uM CoCl2. Cell viability in increasing concentrations of CoCl2 (up to 500uM) was assessed using CFDA and propidium iodide staining. The ratio of live:dead cells decreased dramatically with increasing CoCl2. Phalloidin-FITC was also used to examine cell viability and structure following treatment. With increasing CoCl2 there was evidence for increased disruption of actin filaments. In conclusion, short-term low dose CoCl2 treatment of ventricular preparations results in compromised contractile function. Treatment of non-contractile cardiac fibroblasts with higher concentrations results in decreased ability of cells to proliferate as well as long-term cell damage and death. It is likely that the cardiotoxic effects of CoCl2 are manifest in both contractile and non-contractile cells of the heart. The underlying cellular mechanisms involved have yet to be established

In vitro effects of cobalt ions on CNS derived cell lines

Several neurological symptoms associated with the toxic action of cobalt ions have been reported among patients with metal-on-metal (MoM) hip prostheses made of cobalt chromium (CoCr) alloy. The sporadic nature of these manifestations, combined with the fact that the medical evidence is relatively new, have contributed to poor understanding of the impact of cobalt poisoning on the brain. In the present study, we characterise the cytotoxicity of cobalt ions in human U 373 astrocytoma and SH-SY5Y neuroblastoma cell lines. Metal ion uptake with different cobalt chloride concentrations (0 to 500μM) for three time-points (24, 48 and 72h) was measured using inductively coupled plasma mass spectrometry (ICP-MS), while cell viability was tested with MTT and Neutral Red (NR) assays, and by microscopy. The results show that cobalt uptake is dose and time-dependent (up to 415.23, and 69.47μg/L for astrocytes and neurons, respectively), which corresponds with the significant decrease in cell viability (p<.05) at high cobalt concentrations both for the MTT and NR assays. IC50 values were 438.27±37.73 and 267.36±14.57μM at 48h for astrocytes and neurons, respectively (similar values for 72h), with the MTT assay more sensitive at detecting toxicity, suggesting involvement of redox mechanisms. Morphological changes, such as extensive vacuolization of the cytosol, usually associated with autophagy, were observed in the course of cell death. These results indicate that exposure to cobalt at high concentrations could have deleterious effects on brain cells. Future focus will be on the mechanism(s) responsible for cobalt uptake, which may provide a therapeutic intervention for MoM patients

Cardiac function is compromised in patients with elevated blood cobalt levels secondary to metal-on-metal hip implants

Elevated blood cobalt secondary to metal-on-metal (MoM) hip arthroplasties has been shown to be a risk factor for developing cardiovascular complications including cardiomyopathy. Published case reports document cardiomyopathy in patients with blood cobalt levels as low as 13µg/l. Clinical studies have found conflicting evidence of cobalt-induced cardiomyopathy in patients with MoM hips. The extent of cardiovascular injury, measured by global longitudinal strain (GLS), in patients with elevated blood cobalt levels has not previously been examined. Sixteen patients with documented blood cobalt ion levels above 13µg/l were identified and matched with eight patients awaiting hip arthroplasty with no history of cobalt implants. Patients underwent echocardiogram assessment including GLS. Patients with MoM hip arthroplasties had a mean blood cobalt level of 29µg/l compared to 0.01µg/l in the control group. There was no difference or correlation in EF, left ventricular (LV) end systolic dimension, LV end diastolic dimension, fractional shortening, ventricular wall thickness or E/e’ ratio. However, GLS was significantly reduced in patients with MoM hip arthroplasties compared to those without (-15.2% v -18%, (MoM v control) p= 0.0125). Pearson correlation demonstrated that GLS is significantly correlated with blood cobalt level (r= 0.8742, p=0.0009). This study has demonstrated reduced cardiac function in the presence of normal EF as assessed by GLS in patients with elevated cobalt above 13µg/l. As GLS is a more sensitive measure of systolic function than EF, routine echocardiogram assessment including GLS should be performed in all patients with MoM hip arthroplasties and elevated blood cobalt

Effectiveness and cost-effectiveness of basic versus biofeedback-mediated intensive pelvic floor muscle training for female stress or mixed urinary incontinence: protocol for the OPAL randomised trial

This is the final version. Available on open access from BMJ Publishing Group via the DOI in this recordIntroduction Accidental urine leakage is a distressing problem that affects around one in three women. The main types of urinary incontinence (UI) are stress, urgency and mixed, with stress being most common. Current UK guidelines recommend that women with UI are offered at least 3 months of pelvic floor muscle training (PFMT). There is evidence that PFMT is effective in treating UI, however it is not clear how intensively women have to exercise to give the maximum sustained improvement in symptoms, and how we enable women to achieve this. Biofeedback is an adjunct to PFMT that may help women exercise more intensively for longer, and thus may improve continence outcomes when compared with PFMT alone. A Cochrane review was inconclusive about the benefit of biofeedback, indicating the need for further evidence. Methods and analysis This multicentre randomised controlled trial will compare the effectiveness and cost-effectiveness of PFMT versus biofeedback-mediated PFMT for women with stress UI or mixed UI. The primary outcome is UI severity at 24 months after randomisation. The primary economic outcome measure is incremental cost per quality-adjusted life-year at 24 months. Six hundred women from UK community, outpatient and primary care settings will be randomised and followed up via questionnaires, diaries and pelvic floor assessment. All participants are offered six PFMT appointments over 16 weeks. The use of clinic and home biofeedback is added to PFMT for participants in the biofeedback group. Group allocation could not be masked from participants and healthcare staff. An intention-to-treat analysis of the primary outcome will estimate the mean difference between the trial groups at 24 months using a general linear mixed model adjusting for minimisation covariates and other important prognostic covariates, including the baseline score. Ethics and dissemination Approval granted by the West of Scotland Research Ethics Committee 4 (16/LO/0990). Written informed consent will be obtained from participants by the local research team. Serious adverse events will be reported to the data monitoring and ethics committee, the ethics committee and trial centres as required. A Standard Protocol Items: Recommendations for Interventional Trials checklist and figure are available for this protocol. The results will be published in international journals and included in the relevant Cochrane review. Trial registration number ISRCTN57746448; Pre-results.National Institute for Health Research (NIHR

Reflecting Back to Forge the Path Forward

The JUME editorial team provides an update of the journal\u27s health and progress during the 2021 calendar year and discusses coming changes and opportunities for growth

The End or Beginning? Either Way, the Credits Are Not Rolling Yet!

(First paragraph) Thank you to all our reviewers, editorial board members, authors, and those who chose the Journal of Urban Mathematics Education (JUME) as their outlet of choice this past year. JUME has had many recent successes, and we in the editorial team plan to release the salient performance data for the journal. For JUME to advance its mission, we believe that accountability and transparency are essential. To this end, our readers will from now on receive an annual progress report about JUME in our first issue of each year

Pathway-Wide Association Study Implicates Multiple Sterol Transport and Metabolism Genes in HDL Cholesterol Regulation

Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicate that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels

Effects of acute and chronic cobalt treatment on adult rat cardiomyocyte calcium handling

Patients with cobalt-chromium hip arthroplasties display increased cobalt levels in circulation. Elevated cobalt has been linked to cardiomyopathy, yet the mechanisms underlying cobalt-induced pathology remain unknown. Here, we have examined the effects of acute ( Cardiomyocytes were isolated enzymatically from adult male rats (n=9) and treated acutely for 5min, 1h and 24h with 1, 10 and 100µM CoCl2. After loading with Cal520 AM, calcium transients were measured during electrical pacing at 1Hz and sparks were recorded using confocal microscopy. Chronic cobalt effects were measured in cardiac preparations taken from adult male rats (n=8) injected daily with CoCl2(1mg/kg) for 28 days. A concentration and time-dependent decrease in Ca2+ transient amplitude was evident in cobalt-treated cells compared to controls, with 10μM CoCl2 inducing an amplitude reduction of 15.1±5.4% and 30.0±7.2% at 5min and 1h respectively and 100µM resulting in 25.6±0.05% and 58.8±0.09% reduction at 5min and 1h. Spark frequency was increased with 100µM cobalt relative to control, resulting in 55.4±0.9% and 76.8±1.4% increase at 5min and 1h. RyR2 expression in chronic cobalt-treated ventricular tissue was similar to controls, suggesting RyR2 post-translational modification may account for altered spark frequency. This study demonstrates reduced Ca2+ release and increased RyR2 activation in cardiomyocytes treated acutely with CoCl2. Indications suggest RyR2 phosphorylation may be involved in the negative inotropic effects observed