Targeted screening in the UK:A narrow concept with broad application

A recent report on screening in the UK proposed that the responsibility for recommendations on population and targeted screening programmes should be held by one new integrated advisory body. There is no wide international consensus on the definition of targeted screening. Our review identified and compared the defining components of screening terms: targeted, population, selective, and cascade screening, and case finding. Definitions of targeted screening and population screening were clearly demarcated by the eligible population; targeted and selective screening were found to be conceptually interchangeable; cascade screening, whilst conceptually similar to targeted screening across several components, was only used within the context of genetic diseases. There was little consensus between different definitions of case finding. These comparisons contributed to an updated definition of targeted screening. Considerable overlap between definition components across terms implies that a broad range of disease areas may fall into the remit of the new advisory body

Comparison of radiation dose exposure in patients undergoing percutaneous coronary intervention vs. peripheral intervention

Introduction: Most endovascular techniques are associated with patient and personal exposure to radiation during the procedure. Ionising radiation can cause deterministic effects, such as skin injury, as well as stochastic effects, which increase the longterm risk of malignancy. Endovascular operators need to be aware of radiation danger and take all necessary steps to minimise the risk to patients and staff. Some procedures, especially percutaneous peripheral artery revascularisation, are associated with increased radiation dose due to time-consuming operations. There is limited data comparing radiation dose during percutaneous coronary intervention (PCI) with percutaneous transluminal angioplasty (PTA) of peripheral arteries. Aim: To compare the radiation dose in percutaneous coronary vs. peripheral interventions in one centre with a uniform system of protection methods. Material and methods: A total of 352 patients were included in the study. This included 217 patients undergoing PCI (single and multiple stenting) and 135 patients undergoing PTA (in lower extremities, carotid artery, renal artery, and subclavian artery). Radiation dose, fluoroscopy time, and total procedural time were reviewed. Cumulative radiation dose was measured in gray (Gy) units. Results: The total procedural time was significantly higher in PTA (PCI vs. PTA: 60 (45–85) min vs. 75 (50–100) min), p < 0.001. The radiation dose for PCI procedures was significantly higher in comparison to PTA (PCI vs. PTA: 1.36 (0.83–2.23) Gy vs. 0.27 (0.13–0.46) Gy), p < 0.001. There was no significant difference in the fluoroscopy time (PCI vs. PTA: 12.9 (8.2–21.5) min vs. 14.4 (8.0–22.6) min), p = 0.6. The analysis of correlation between radiation dose and fluoroscopy time in PCI and PTA interventions separately shows a strong correlation in PCI group (r = 0.785). However, a weak correlation was found in PTA group (r = 0.317). Conclusions: The radiation dose was significantly higher during PCI in comparison to PTA procedures despite comparable fluoroscopy time and longer total procedure time in PTA. Fluoroscopy time is a reliable parameter to control the radiation dose exposure in coronary procedures. The increasing complexity of endovascular interventions has resulted in the increase of radiation dose exposure during PCI procedures

Intima-media thickness and ankle-brachial index are correlated with the extent of coronary artery disease measured by the SYNTAX score

Introduction: The extent of peripheral artery disease (PAD) measured by the ankle-brachial index (ABI) and intima-media thickness (IMT) is correlated with the complexity of coronary artery disease (CAD) in stable angina patients. However, data regarding patients with acute coronary syndromes are still lacking. Aim: To compare coronary complexity measured by the SYNTAX score in patients with and without PAD presenting with myocardial infarction (MI). Material and methods: Both ABI and IMT were measured in 101 consecutive patients who underwent primary diagnostic due to MI. Patients were divided into three tertile groups depending on the SYNTAX score (0–4; 5–11; 12 and more points). Results: Mean ABI in the general population was 0.9 ±0.26, mean IMT was 0.8 ±0.3 mm and mean SYNTAX score was 7.8 ±5.4 points. We found significant correlations between ABI and SYNTAX score (p = 0.01), IMT and SYNTAX score (p < 0.001), and IMT and ABI (p < 0.001). The highest mean values of IMT (p < 0.001) and lowest mean values of ABI (p = 0.015) were found in patients in the highest SYNTAX score group. When analyzing receiver operating characteristics (ROC) curves, IMT had greater specificity and sensitivity than ABI. Conclusions: Both IMT and ABI are correlated with SYNTAX score (positively for IMT and negatively for ABI values). In our study, IMT was a better predictor of SYNTAX score than ABI. Our study suggests that the higher rate of cardiovascular events in patients with PAD presenting with MI may be partially explained by greater coronary lesion complexity

Repressive gene regulation synchronizes development with cellular metabolism

Metabolic conditions affect the developmental tempo of animals. Developmental gene regulatory networks (GRNs) must therefore synchronize their dynamics with a variable timescale. We find that layered repression of genes couples GRN output with variable metabolism. When repressors of transcription or mRNA and protein stability are lost, fewer errors in Drosophila development occur when metabolism is lowered. We demonstrate the universality of this phenomenon by eliminating the entire microRNA family of repressors and find that development to maturity can be largely rescued when metabolism is reduced. Using a mathematical model that replicates GRN dynamics, we find that lowering metabolism suppresses the emergence of developmental errors by curtailing the influence of auxiliary repressors on GRN output. We experimentally show that gene expression dynamics are less affected by loss of repressors when metabolism is reduced. Thus, layered repression provides robustness through error suppression and may provide an evolutionary route to a shorter reproductive cycle

Repressive gene regulation synchronizes development with cellular metabolism

Metabolic conditions affect the developmental tempo of animals. Developmental gene regulatory networks (GRNs) must therefore synchronize their dynamics with a variable timescale. We find that layered repression of genes couples GRN output with variable metabolism. When repressors of transcription or mRNA and protein stability are lost, fewer errors in Drosophila development occur when metabolism is lowered. We demonstrate the universality of this phenomenon by eliminating the entire microRNA family of repressors and find that development to maturity can be largely rescued when metabolism is reduced. Using a mathematical model that replicates GRN dynamics, we find that lowering metabolism suppresses the emergence of developmental errors by curtailing the influence of auxiliary repressors on GRN output. We experimentally show that gene expression dynamics are less affected by loss of repressors when metabolism is reduced. Thus, layered repression provides robustness through error suppression and may provide an evolutionary route to a shorter reproductive cycle

SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington's Disease Phenotypes In Vivo

Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD[superscript +]-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis – a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.American Parkinson Disease Association, Inc. (Fellowship)Johnson & Johnson. Pharmaceutical Research & Development (Fellowship

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

The effect of selenium, zinc and copper on the excretion of urinary modified nucleobases in rats treated with prostate cancer cells

Given the strong associations between diet and cancer risk, there is considerable scientific interest in determining whether dietary factors associated with prostate cancer cell implantation may influence epigenetic alternations. The aim of the research was to assess impact of selected trace elements (selenium, zinc and copper) on the kinetics of changes (10-13-14-21 week of life cycle of rats) in the level of 7-methylguanine, 3-methyladenine, 1-methylguanine and 8-oxo-guanine in the urine of rats with implanted prostate cancer cells (LNCaP). Modified nucleobases were determined by validated high performance liquid chromatography coupled to mass spectrometry (LC-MS/MS) method using multiple reaction monitoring (MRM) mode. In the presented model the implantation of rats with cancer cells did not affect the level of the examined biomarkers in the rats’ urine. The level of methyl derivatives was statistically significantly reduced with the age of the examined rats. The implantation of rats with cancer cells results in the appearance of tumors in 71% of the rats obtaining the standard diet and respectively in 25% of those supplemented with selenium. Supplementation with selenium affects both the effectiveness of tumor induction and the concentration of 7-MeG, 3-MeA, 1-MeG and 8-oxoG in urine of the examined rats. These findings show that modified nucleosides can play an important role in cancer prevention