Recent research has used cardiovascular risk scores intended to estimate “total cardiovascular disease (CVD) risk” in individuals to assess the distribution of risk within populations. The research suggested that the adoption of the total risk approach, in comparison to treatment decisions being based on the level of a single risk factor, could lead to reductions in expenditure on preventive cardiovascular drug treatment in low- and middle-income countries. So that the patient benefit associated with savings is highlighted.
This study used data from national STEPS surveys (STEPwise Approach to Surveillance) conducted between 2005 and 2010 in Cambodia, Malaysia and Mongolia of men and women aged 40–64 years. The study compared the differences and implications of various approaches to risk estimation at a population level using the World Health Organization/International Society of Hypertension (WHO/ISH) risk score charts. To aid interpretation and adjustment of scores and inform treatment in individuals, the charts are accompanied by practice notes about risk factors not included in the risk score calculations. Total risk was calculated amongst the populations using the charts alone and also adjusted according to these notes. Prevalence of traditional single risk factors was also calculated.
The prevalence of WHO/ISH “high CVD risk” (≥20% chance of developing a cardiovascular event over 10 years) of 6%, 2.3% and 1.3% in Mongolia, Malaysia and Cambodia, respectively, is in line with recent research when charts alone are used. However, these proportions rise to 33.3%, 20.8% and 10.4%, respectively when individuals with blood pressure > = 160/100 mm/Hg and/or hypertension medication are attributed to “high risk”. Of those at “moderate risk” (10- < 20% chance of developing a cardio vascular event over 10 years), 100%, 94.3% and 30.1%, respectively are affected by at least one risk-increasing factor. Of all individuals, 44.6%, 29.0% and 15.0% are affected by hypertension as a single risk factor (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg or medication).
Used on a population level, cardiovascular risk scores may offer useful insights that can assist health service delivery planning. An approach based on overall risk without adjustment of specific risk factors however, may underestimate treatment needs.
At the individual level, the total risk approach offers important clinical benefits. However, countries need to develop appropriate clinical guidelines and operational guidance for detection and management of CVD risk using total CVD-risk approach at different levels of health system. Operational research is needed to assess implementation issues.
Posttranslational arginylation mediated by arginyltransferase (ATE1) is an emerging major regulator of embryogenesis and cell physiology. Impairments of ATE1 are implicated in congenital heart defects, obesity, cancer, and neurodegeneration making this enzyme an important therapeutic target, whose potential has been virtually unexplored. Here we report the development of a biochemical assay for identification of small molecule inhibitors of ATE1 and application of this assay to screen a library of 3280 compounds. Our screen identified two compounds which specifically affect ATE1-regulated processes in vivo, including tannic acid, which has been previously shown to inhibit protein degradation and angiogenesis and to act as a therapeutic agent in heart disease and cancer. Our data suggest that these actions of tannic acid are mediated by its direct effect on ATE1, which regulates protein degradation and angiogenesis in vivo.
ATE1 inhibitors; arginylation; tannic acid; cell motility; angiogenesis
Mercury is an environmental toxicant that can disrupt brain development. However, while progress has been made in defining its neurotoxic effects, we know far less about available therapies that can effectively protect brain in exposed individuals. We previously developed an animal model in which we defined the sequence of events underlying neurotoxicity: Methylmercury (MeHg) injection in postnatal rat acutely induced inhibition of mitosis and stimulated apoptosis in the hippocampus, that later resulted in intermediate term deficits in structure size and cell number. NAC is the N-acetyl derivative of L-cysteine used clinically for treatment of drug intoxication. Here, based on its known efficacy in promoting MeHg urinary excretion, we evaluated NAC for protective effects in the developing brain. In immature neurons and precursors MeHg (3µM) induced a >50% decrease in DNA synthesis at 24hr, an effect that was completely blocked by NAC co-incubation. In vivo, injection of MeHg (5µg/gbw) into 7 day-old rats induced a 22% decrease in DNA synthesis in whole hippocampus and a 4-fold increase in activated caspase-3 immunoreactive cells at 24hr, and reduced total cell numbers by 13% at 3 weeks. Treatment of MeHg exposed rats with repeated injections of NAC abolished MeHg toxicity. NAC prevented the reduction in DNA synthesis and the marked increase in caspase-3 immunoreactivity. Moreover, the intermediate term decrease in hippocampal cell number provoked by MeHg was fully blocked by NAC. Altogether, these results suggest that MeHg toxicity in the perinatal brain can be ameliorated by using NAC, opening potential avenues for therapeutic intervention.
mercury; hippocampus; N-acetyl cysteine; neurogenesis; programmed cell death
Intranasal exposure to the heavy metal cadmium has been linked to olfactory dysfunction and neurotoxicity. Here, we combine optical imaging of in vivo neurophysiology, genetically defined anatomical tract tracing, mass spectrometry, and behavioral psychophysical methods to evaluate the persistent harmful effects of acute intranasal exposure to cadmium in a mouse model and to investigate the functional consequences of sensory rehabilitation training. We find that an acute intranasal instillation of cadmium chloride leads to an accumulation of cadmium in the brain's olfactory bulb that persists for at least 4 weeks. This is accompanied by persistent severe pathophysiology of the olfactory nerve, a gradual reduction in axonal projections from the olfactory epithelium, and complete impairment on an olfactory detection task. Remarkably, 2 weeks of odorant-guided operant conditioning training proved sufficient to restore olfactory detection performance to control levels in cadmium-exposed mice. Optical imaging from rehabilitated mice showed that this training did not cause any detectable restoration of olfactory nerve function, suggesting that the recovery of function was mediated by central neuroplasticity in which the brain learned to interpret the degraded sensory input. These data demonstrate that sensory learning can mask even severe damage from neurotoxicants and suggest that explicit sensory training may be useful in rehabilitation of olfactory dysfunction.
rehabilitation; sensory learning; heavy metal; olfactory; neuroplasticity; neurotoxicity
Despite extensive research and interest in endocrine disruptors, there are essentially no epidemiologic studies of estrogenic mycotoxins, such as zeranol and zearalenone (ZEA). ZEA mycoestrogens are present in grains and other plant foods through fungal contamination, and in animal products (e.g., meat, eggs, dairy products) through deliberate introduction of zeranol into livestock to enhance meat production, or by indirect contamination of animals through consumption of contaminated feedstuff. Zeranol is banned for use in animal husbandry in the European Union and other countries, but is still widely used in the US. Surprisingly, little is known about the health effects of these mycoestrogens, including their impact on puberty in girls, a period highly sensitive to estrogenic stimulation.
OBJECTIVES AND METHODS
We conducted a cross-sectional analysis among 163 girls, aged 9 and 10 years, participating in the Jersey Girl Study to measure urinary mycoestrogens and their possible relationship to body size and development.
We found that mycoestrogens were detectable in urine in 78.5% of the girls, and that urinary levels were predominantly associated with beef and popcorn intake. Furthermore, girls with detectable urinary ZEA mycoestrogen levels tended to be shorter and less likely to have reached the onset of breast development.
Our findings suggest that ZEA mycoestrogens may exert anti-estrogenic effects similar to those reported for isoflavones. To our knowledge, this was the first evaluation of urinary mycoestrogens and their potential health effects in healthy girls. However, our findings need replication in larger studies with more heterogeneous populations, using a longitudinal approach.
mycoestrogens; zearalenone; zeranol; thelarche; height; weight
Benign diseases of the prostate are common in the general male population, and prostate cancer is the most common cancer in men. Uncertaintyastothe nature of the association between benign and malignant disease is a source of concern for patients and clinicians.
To determine the likelihood of men with benign prostate disease developing prostate cancer compared with men without disease.
Incident matched case-control study
All incident cases of prostate cancer (n = 984) were identified in a nationally representative community-based population, and each was matched by age with two controls with no prostate cancer (n = 1968). Participants' records of the previous 5 years were searched for diagnoses of benign prostate disease. Analyses investigated an a priori hypothesis that clinicians may record disease as benign until proven to be malignant, causing misleading significant associations between benign and malignant diagnoses.
There was a significant association between a diagnosis of prostate cancer and a benign diagnosis at any time in the previous 5 years: odds ratio (OR) 1.57 (95% confidence interval [CI] = 1.32 to 1.88). However, there was no significant association when benign diagnoses within 6 months and within 12 months of cancer diagnoses were excluded: OR 1.19 (95% CI = 0.97 to 1.46) and OR 1.00 (95% CI = 0.79 to 1.27) respectively.
Findings from this study suggest that unless prostate cancer is detected within 6 months, men diagnosed for the first time with benign disease are at no greater risk of prostate cancer than those with no recorded prostate disease.
primary health care; prognosis; prostatic hyperplasia; prostatic neoplasms; prostate-specific antigen
Inguinal hernia is a common condition and its repair (herniorrhaphy) is one of the most commonly performed procedures in general surgery. The Lichtenstein herniorrhaphy technique is a widely used and effective surgery that uses mesh to reinforce the area of weakness. Although a wide range of mesh sizes are available for use in hernia repair, in low-resource health care settings the provision of multiple products may not be supportable and it may be necessary for the provision and use of a single mesh size. This study aimed to determine whether the recommended 7.0 cm x 15.0 cm size is an appropriate single mesh size.
In order to determine the optimal mesh size according to recommended surgical practices, in vivo measurements of key dimensions of the inguinal floor were taken in patients undergoing herniorrhaphy.
Measurements were taken in 43 patients: 40 men and 3 women, mean age 43 years (SD 13.6); 39 with indirect hernias, 4 with direct. Allowing for recommended mesh overlaps, the optimal mesh size for provision to be appropriate for the majority of patients was determined to be 8.5 cm x 14.0 cm, 21% wider than the mesh size currently recommended for use in Lichtenstein herniorrhaphy.
An appropriate size for routine provision in low-resource settings, or other settings where the provision of several mesh sizes is not supportable, may be 8.5 cm x 14.0 cm.
Inguinal hernia; Herniorrhaphy; Mesh; Low and middle income countries
Pesticide exposure has been implicated as an environmental risk factor for the development of Parkinson’s disease (PD). However, few studies have identified specific pesticides. Previously, we identified elevated serum levels of the organochlorine pesticide β-hexachlorocyclohexane (β-HCH) in PD patients from a small clinical sample. Here, we conducted a case-control study to confirm the association between β-HCH and PD in a larger sample size (n=283) with serum samples of PD patients and controls obtained from UT Southwestern Medical Center and Emory University. Samples were obtained from two discrete periods at both sites, 2001–2003 and 2006–2008, and were analyzed for β-HCH levels. Adjusted odds ratios (ORs) for PD were estimated using logistic regression and generalized estimating equations. The mean serum β-HCH level across all cohorts in this study was 22.3 ng/mg cholesterol (Range: 0 to 376.7), and the levels were significantly higher between samples collected in 2001–2003 vs. 2006–2008. After controlling for age and gender, the OR for increased risk of PD for every 1 ng/mg increase in serum β-HCH ranged from 1.02 – 1.12 across the four different cohorts, and 1.03 (95% CI: 1.00–1.07, p value = 0.031) in the pooled analysis. Furthermore, the OR for increased risk of PD of subjects having serum β-HCH levels above the inter-quartile range of 39.08 ng/mg cholesterol was 2.85 (95% CI: 1.8, 4.48; p value < 0.001). These data are consistent with environmental decreases in β-HCH levels between 2001 and 2008, but they indicate that elevated levels of serum β-HCH are still associated with heightened risk for PD.
organochlorine; pesticide; Parkinson’s disease; beta-hexachlorocyclohexane
Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 µg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes.
Exposure to pesticides has been reported to increase the risk of Parkinson disease (PD), but identification of the specific pesticides is lacking. Three studies have found elevated levels of organochlorine pesticides in postmortem PD brains.
To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD.
An academic medical center.
Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease.
Main Outcome Measures
Levels of 16 organochlorine pesticides in serum samples.
β-Hexachlorocyclohexane (β-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of β-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of β-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67–11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum β-HCH and PD.
These data suggest that β-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of β-HCH as a etiologic agent for some cases of PD.
To assess the coverage of individual-based primary prevention strategies for cardiovascular disease (CVD) in Cambodia and Mongolia: specifically the early identification of hypertension and diabetes mellitus, major proximate physiological CVD risk factors, and management with pharmaceutical and lifestyle advice interventions.
Analysis of data collected in national cross-sectional STEPS surveys in 2009 (Mongolia) and 2010 (Cambodia) involving participants aged 25-64 years: 5433 in Cambodia and 4539 in Mongolia.
Mongolia has higher prevalence of CVD risk factors than Cambodia --hypertension (36.5% versus 12.3%), diabetes (6.3% versus 3.1%), hypercholesterolemia (8.5% versus 3.2%), and overweight (52.5% versus 15.5%). The difference in tobacco smoking was less notable (32.1% versus 29.4%).
Coverage with prior testing for blood glucose in the priority age group 35-64 years remains limited (16.5% in Cambodia and 21.7% in Mongolia). Coverage is higher for hypertension. A large burden of both hypertension and diabetes remains unidentified at current strategies for early identification: only 45.4% (Cambodia) to 65.8% (Mongolia) of all hypertensives and 22.8% (Mongolia) to 50.3% (Cambodia) of all diabetics in the age group 35-64 years had been previously diagnosed.
Approximately half of all hypertensives and of all diabetics in both countries were untreated. 7.2% and 12.2% of total hypertensive population and 5.9% and 16.1% of total diabetic population in Cambodia and Mongolia, respectively, were untreated despite being previously diagnosed.
Only 24.1% and 28.6% of all hypertensives and 15.9% and 23.9% of all diabetics in Mongolia and Cambodia, respectively were adequately controlled. Estimates suggest deficits in delivery of important advice for lifestyle interventions.
Multifaceted strategies are required to improve early identification, initiation of treatment and improving quality of treatment for common CVD risk factors. Periodic population-based surveys including questions on medical and treatment history and the context of testing and treatment can facilitate monitoring of individual-based prevention strategies.
Epigenetic modifications, such as DNA methylation, play key roles in transcriptional regulation of gene expression. More recently, global DNA methylation levels have been documented to be altered in several diseases, including cancer, and as the result of exposure to environmental toxicants. Based on the potential use of global DNA methylation status as a biomarker of disease status and exposure to environmental toxicants, we sought to develop a rapid, sensitive, and precise analytical method for the quantitative measurement of global DNA methylation status using ultra performance liquid chromatography with detection by ion trap tandem mass spectrometry. Using a fused-core silica column, 2′-deoxyguanosine (2dG) and 5-methyl-2′-deoxycytidine (5mdC) were resolved in less than 1 minute, with detection limits of 0.54 and 1.47 fmol for 5mdC and 2dG respectively. The accuracy of detection was 95% or above and the day-to-day coefficient of variations was found to be 3.8%. The method was validated by quantification of global DNA methylation status following treatment of cells with the DNA methyltransferase inhibitor 5-aza-2′deoxycytidine, which reduced DNA methylation from 3.1% in control cells to 1.1% in treated cells. The sensitivity and high throughput of this method rend it suitable for large scale analysis of epidemiological or clinical DNA samples.
Ultra performance liquid chromatography (UPLC); electrospray ionization ion trap mass spectrometry (ESI ITMS); global DNA methylation
Following an AMI, it is important for patients and their physicians to appreciate the subsequent risk of death, and the potential benefits of invasive cardiac procedures and secondary preventive therapy. Studies, to-date, have focused largely on high-risk populations. We wished to determine the risk of death in a population-derived cohort of 2,887 patients after a first acute myocardial infarction (AMI).
Logistic regression and survival analysis were conducted to investigate the effect of different baseline characteristics, pharmacological therapies and revascularization procedures on coronary heart disease (CHD) and all-cause mortality outcomes.
Within five years 44.4% of patients died (27.1% short-term [<30 days] and 23.7% longer-term [≥30 days]). Percutaneous transluminal coronary angioplasty (Adjusted Hazards Ratio (AHR) = 0.49, 95% Confidence Interval (CI) 0.26–0.93), β-blockers (AHR = 0.58, 95%CI 0.46–0.74) and statins (AHR = 0.60, 95%CI 0.47–0.77) were all associated with significant reductions in longer-term CHD-related mortality. However, not all patients received secondary preventive therapy (8.7%). Diabetes (AHR = 1.83, 95%CI 1.43–2.34), stroke (AHR = 1.73, 95%CI 1.35–2.22), heart failure (AHR = 1.69, 95%CI 1.28–2.22), smoking (AHR = 1.72, 95%CI 1.18–2.51) and obesity (>30 kg/m2; AHR = 1.39, 95%CI 1.01–1.90) increased the risk of longer-term mortality independent of other risk factors.
It is encouraging that the coronary procedure PTCA and pharmacological secondary prevention therapies were found to be strongly associated with an important reduced risk of subsequent death, although not all patients received these interventions. Smoking, being obese and having cardiovascular related disease at baseline were also associated with an increased likelihood of longer-term mortality, independent of other baseline characteristics. Thus, the provision of smoking cessation, advice on diet (for obese patients) and optimal treatment is likely to be crucial for reducing mortality in all patients after AMI.
Improper catheterization can lead to urethral injury. Yet research from four continents suggests training of junior doctors in catheterization is insufficient. European research suggests a majority of catheterization related morbidities occur when the procedure is performed by interns.
To assess the knowledge and practices of medical interns relating to urethral catheterization and iatrogenic urethral injury secondary to traumatic catheter insertion, a questionnaire survey was conducted of all first year medical interns at a tertiary national university hospital in the Philippines. The questionnaire contained 17 items covering 4 areas: methods of training in catheterization and level of experience; perceived adequacy of training; theoretical knowledge of catheterization; the mechanisms of catheter-related urethral injury.
225/240 interns (94%) completed the survey (130 (57.8%) female). 125 (55.6%) responded that they had adequate theoretical training and 150 (66.7%) adequate practical training. All had performed more than 10 catheterizations and 204 (90%) were supervised when they first performed catheterization. Despite relatively high levels of experience and confidence, deficits were identified in detailed knowledge of correct catheterization procedures and of risks associated with urethral injury.
More thorough training of incoming medical interns in urinary catheterization may help to reduce the risk of complications and injury. Training should be universal and thought given to its timing within the curriculum. Training should include step by step instruction in the process, emphasis on history taking and awareness of factors associated with increased risk of urethral injury.
urinary catheterization; education; medical; injuries; urethral
Urinary incontinence is an important health problem to the individual sufferer and to health services. Stress and stress predominant mixed urinary incontinence are increasingly managed by surgery due to advances in surgical techniques. Despite the lack of evidence for its clinical utility, most clinicians undertake invasive urodynamic testing (IUT) to confirm a functional diagnosis of urodynamic stress incontinence before offering surgery for this condition. IUT is expensive, embarrassing and uncomfortable for women and carries a small risk. Recent systematic reviews have confirmed the lack of high quality evidence of effectiveness.
The aim of this pilot study is to test the feasibility of a future definitive randomised control trial that would address whether IUT alters treatment decisions and treatment outcome in these women and would test its clinical and cost effectiveness.
This is a mixed methods pragmatic multicentre feasibility pilot study with four components:-
(a) A multicentre, external pilot randomised trial comparing basic clinical assessment with non-invasive tests and IUT. The outcome measures are rates of recruitment, randomisation and data completion. Data will be used to estimate sample size necessary for the definitive trial.
(b) Qualitative interviews of a purposively sampled sub-set of women eligible for the pilot trial will explore willingness to participate, be randomised and their overall trial experience.
(c) A national survey of clinicians to determine their views of IUT in this context, the main outcome being their willingness to randomise patients into the definitive trial.
(d) Qualitative interviews of a purposively sampled group of these clinicians will explore whether and how they use IUT to inform their decisions.
The pilot trial will provide evidence of feasibility and acceptability and therefore inform the decision whether to proceed to the definitive trial. Results will inform the design and conduct of the definitive trial and ensure its effectiveness in achieving its research aim.
Trial registration number
Current Controlled Trials ISRCTN71327395 assigned 7th June 2010.
Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na+ channels and T-type Ca2+ channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC50 of 25 μM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP+), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.
zonisamide; epilepsy; MPTP; MAO-B; mice; Parkinson's disease
To evaluate differences between adults who consent to participate in observational research and those who do not.
Prospective, population‐based cohort study.
35 randomised Irish general practices.
1609 adults with ischaemic heart disease identified in 2000–1.
Medical records search, postal questionnaire and consent form in 2005–6.
Main outcome measures
Differences in demographic and prognostic risk factors between consenters and non‐consenters.
At follow‐up, charts were located for 1592 patients (98.9%). Questionnaires were sent to 1269 patients and 876 were returned (69%). Of these, 574 (65.5%) gave consent for participation in further research. Logistic regression identified four characteristics as independently positively predictive of consent to participation in further research among questionnaire responders: having undergone percutaneous transluminal coronary angioplasty was associated with an increased odds of consent, with an odds ratio (OR) of 1.77 (95% CI 1.09 to 2.86), as was a last recorded blood pressure <140/90 mm Hg (OR = 1.45 (1.00 to 2.09)), a last recorded total cholesterol level <5 mmol/l (OR = 1.71 (1.16 to 2.54)) and being an ex‐smoker rather than a current smoker or non‐smoker (OR = 1.73 (1.17 to 2.57)).
This research demonstrates the potential impact of consent bias in observational research on ischaemic heart disease, a disease of everyday clinical importance in Europe. It demonstrates that clinically important prognostic variables may be associated with consent preferences. Future cohorts, dependent upon prior written consent, may contain disproportionate numbers of those who have made healthy lifestyle decisions, have previously benefited from treatment or whose clinical risk factors are already well managed. As a result, the generalisability of such research may be diminished and the effects of treatments over‐ or underestimated.
selection bias; consent; observational research; ischaemic heart disease
Numerous preclinical, epidemiological and clinical studies have suggested the benefits of vitamin D and its analogs for the prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1α,25(OH)2D3, the hormonally active form of vitamin D. To identify vitamin D analogs with better efficacy and low toxicity, we have tested more than 60 novel Gemini vitamin D analogs with a unique structure of two side chains for growth inhibition of breast cancer cells. Our initial studies found that some Gemini analogs are many-fold more active than 1α,25(OH)2D3 in growth inhibition assay. In vivo experiments were designed to study the inhibitory effect of selected Gemini vitamin D analogs against mammary carcinogenesis by using (a) an N-methyl-N-nitrosourea-induced estrogen receptor (ER)-positive mammary tumor model and (b) an MCF10DCIS.com xenograft model of ER-negative mammary tumors. Among vitamin D analogs we tested, Gemini 0072 [1α,25-dihydroxy-20S-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] and Gemini 0097 [1α,25-dihydroxy-20R-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] administration inhibited by 60% the NMU-induced mammary tumor burden compared to the NMU-treated control group, but these compounds were devoid of hypercalcemia toxicity. In an ER-negative xenograft model, Gemini 0097 significantly suppressed tumor growth without hypercalcemia toxicity. We found that the inhibitory effect of Gemini 0097 was associated with an increased level of cyclin dependent kinase inhibitor p21 and the insulin-like growth factor binding protein 3 in both ER-positive and ER-negative mammary tumors. Our results suggest that Gemini vitamin D analogs may be potent agents for the prevention and treatment of both ER-positive and ER-negative breast cancer without hypercalcemia toxicity.
Gemini Vitamin D; estrogen receptor; mammary tumorigenesis; IGFBP-3; Smad
(−)-Epigallocatechin-3- gallate (EGCG), the most abundant and biologically active compound in tea, has been proposed to have beneficial health effects, including prevention of cancer and heart disease. Different mechanisms of action of EGCG have been proposed, based mainly on studies in cell line systems, in which EGCG is not stable. It has been proposed that oxidation of EGCG and its production of reactive oxygen species are responsible for the biological activities such as receptor inactivation and telomerase inhibition. It is unclear, however, if this phenomenon occurs in vivo. In the present study, the stability of EGCG and product formation in Tris-HCl buffer was investigated using real- time mass spectrometry combined with tandem mass ion mapping. With real-time mass data acquisition, we demonstrate for the first time the formation of EGCG quinone, EGCG dimer quinone, and other related compounds. The structural information of the major appearing ions was provided by tandem mass analysis of each ion. A mechanism for the autoxidation of EGCG was proposed based on the structural information of these ions. None of these oxidation products were observed in the plasma samples of mice after treatment with 50 mg/kg EGCG, i.p. daily for 3 days. Instead, the methylated and conjugated metabolites of EGCG were observed. Therefore the roles of EGCG autoxidation in the biological activities of this compound in vivo remain to be investigated further.
EGCG quinone; EGCG dimers; real-time mass spectrometry; tandem mass ion mapping; autoxidation; tea; mice
Objective To ascertain the risk of acute myocardial infarction, invasive cardiac procedures, and mortality among patients with newly diagnosed angina over five years.
Design Incident cohort study of patients with primary care data linked to secondary care and mortality data.
Setting 40 primary care practices in Scotland.
Participants 1785 patients with a diagnosis of angina as their first manifestation of ischaemic heart disease, 1 January 1998 to 31 December 2001.
Main outcome measures Adjusted hazard ratios for acute myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, death from ischaemic heart disease, and all cause mortality, adjusted for demographics, lifestyle risk factors, and comorbidity at cohort entry.
Results Mean age was 62.3 (SD 11.3). Male sex was associated with an increased risk of acute myocardial infarction (hazard ratio 2.01, 95% confidence interval 1.35 to 2.97), death from ischaemic heart disease (2.80, 1.73 to 4.53), and all cause mortality (1.82, 1.33 to 2.49). Increasing age was associated with acute myocardial infarction (1.04, 1.02 to 1.06, per year of age increase), death from ischaemic heart disease (1.09, 1.06 to 1.11, per year of age increase), and all cause mortality (1.09, 1.07 to 1.11, per year of age increase). Smoking was associated with subsequent acute myocardial infarction (1.94, 1.31 to 2.89), death from ischaemic heart disease (2.12, 1.32 to 3.39), and all cause mortality (2.11, 1.52 to 2.95). Obesity was associated with death from ischaemic heart disease (2.01, 1.17 to 3.45) and all cause mortality (2.20, 1.52 to 3.19). Previous stroke was associated with all cause mortality (1.78, 1.13 to 2.80) and chronic kidney disease with death from ischaemic heart disease (5.72, 1.74 to 18.79). Men were more likely than women to have coronary artery bypass grafting or percutaneous transluminal coronary angioplasty after a diagnosis of angina; older people were less likely to receive percutaneous transluminal coronary angioplasty. Acute myocardial infarction after a diagnosis of angina was associated with an increased risk of death from ischaemic heart disease and all cause mortality (8.84 (5.31 to 14.71) and 4.23 (2.78 to 6.43), respectively). Neither of the invasive cardiac procedures significantly reduced the subsequent risk of all cause mortality.
Conclusions In this sample of people with incident angina from primary care, there were sex differences in survival and age and sex differences in the provision of revascularisation after a diagnosis. Acute myocardial infarction after a diagnosis of angina was strongly predictive of mortality. To minimise adverse outcomes, optimal preventive treatments should be used in patients with angina.
Most patients managed in primary care have more than one condition. Multimorbidity presents challenges for the patient and the clinician, not only in terms of the process of care, but also in terms of management and risk assessment.
To examine the effect of the presence of chronic kidney disease and diabetes on mortality and morbidity among patients with established cardiovascular disease.
Design of study
Retrospective cohort study.
Random selection of 35 general practices in the west of Ireland.
A practice-based sample of 1609 patients with established cardiovascular disease was generated in 2000–2001 and followed for 5 years. The primary endpoint was death from any cause and the secondary endpoint was a cardiovascular composite endpoint that included death from a cardiovascular cause or any of the following cardiovascular events: myocardial infarction, heart failure, peripheral vascular disease, or stroke.
Risk of death from any cause was significantly increased in patients with increased multimorbidity (P<0.001), as was the risk of the cardiovascular composite endpoint (P<0.001). Patients with cardiovascular disease and diabetes had a similar survival pattern to those with cardiovascular disease and chronic kidney disease, but experienced more cardiovascular events.
Level of multimorbidity is an independent predictor of prognosis among patients with established cardiovascular disease. In such patients, the presence of chronic kidney disease carries a similar mortality risk to diabetes. Multimorbidity may be a useful factor in prioritising management of patients in the community with significant cardiovascular risk.
chronic kidney disease; coronary disease; diabetes; mortality; multimorbidity; primary care
Tumor necrosis factor-α (TNF-α) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti–TNF-α drugs such as etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are a new class of drugs designed to induce therapeutically favorable splice variants of targeted genes. In this work, we used locked nucleic acid (LNA)–based SSOs to modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous expression from the membrane-bound, functional form to a soluble, secreted form (Δ7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-α, and altered disease in two mouse models: TNF-α-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-α antagonist by oligonucleotide-induced splicing modulation.
Cell-penetrating peptides (CPPs), containing arginine (R), 6-aminohexanoic acid (X), and/or β-alanine (B) conjugated to phosphorodiamidate morpholino oligomers (PMOs), enhance their delivery in cell culture. In this study, the potency, functional biodistribution, and toxicity of these conjugates were evaluated in vivo, in EGFP-654 transgenic mice that ubiquitously express the aberrantly spliced EGFP-654 pre-mRNA reporter. Correct splicing and enhanced green fluorescence protein (EGFP) upregulation serve as a positive readout for peptide-PMO (PPMO) entry into cells and access to EGFP-654 pre-mRNA in the nucleus. Intraperitoneal injections of a series of PPMOs, A-N (12 mg/kg), administered once a day for four successive days resulted in splicing correction in numerous tissues. PPMO-B was highly potent in the heart, diaphragm, and quadriceps, which are key muscles in the treatment of Duchenne muscular dystrophy. We therefore investigated PPMO M23D-B, designed to force skipping of stop-codon containing dystrophin exon 23, in an mdx mouse model of the disease. Systemic delivery of M23D-B yielded persistent exon 23 skipping, yielding high and sustained dystrophin protein expression in body-wide muscles, including cardiac muscle, without detectable toxicity. The rescued dystrophin reduced serum creatinine kinase to near-wild-type levels, indicating improvement in muscle integrity. This is the first report of oligonucleotide-mediated exon skipping and dystrophin protein induction in the heart of treated animals.