Both Paraoxonase-1 Genotype and Activity Do Not Predict the Risk of Future Coronary Artery Disease; the EPIC-Norfolk Prospective Population Study

Background

Paraoxonase-1 (PON1) is an antioxidant enzyme, that resides on high-density lipoprotein (HDL). PON1-activity, is heavily influenced by the PON1-Q192R polymorphism. PON1 is considered to protect against atherosclerosis, but it is unclear whether this relation is independent of its carrier, HDL. In order to evaluate the atheroprotective potential of PON1, we assessed the relationships among PON1-genotype, PON1-activity and risk of future coronary artery disease (CAD), in a large prospective case-control study.

Methodology/Principal Findings

Cases (n = 1138) were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n = 2237) were matched by age, sex and enrollment time. PON1-activity was similar in cases and controls (60.7±45.3 versus 62.6±45.8 U/L, p = 0.3) and correlated with HDL-cholesterol levels (r = 0.16, p<0.0001). The PON1-Q192R polymorphism had a profound impact on PON1-activity, but did not predict CAD risk (Odds Ratio [OR] per R allele 0.98[0.84–1.15], p = 0.8). Using conditional logistic regression, quartiles of PON1-activity showed a modest inverse relation with CAD risk (OR for the highest versus the lowest quartile 0.77[0.63–0.95], p = 0.01; p-trend = 0.06). PON1-activity adjusted for Q192R polymorphism correlated better with HDL-cholesterol (r = 0.26, p<0.0001) and more linearly predicted CAD risk (0.79[0.64–0.98], p = 0.03; p-trend = 0.008). However, these relationships were abolished after adjustment for HDL (particles-cholesterol-size) and apolipoproteinA-I (0.94[0.74–1.18], p-trend = 0.3).

Conclusions/Significance

This study, shows that PON1-activity inversely relates to CAD risk, but not independent of HDL, due to its close association with the HDL-particle. These data strongly suggest that a low PON1-activity is not a causal factor in atherogenesis.     

Cost-Effectiveness of an Opportunistic Screening Programme and Brief Intervention for Excessive Alcohol Use in Primary Care

Background

Effective prevention of excessive alcohol use has the potential to reduce the public burden of disease considerably. We investigated the cost-effectiveness of Screening and Brief Intervention (SBI) for excessive alcohol use in primary care in the Netherlands, which is targeted at early detection and treatment of ‘at-risk’ drinkers.

Methodology and Results

We compared a SBI scenario (opportunistic screening and brief intervention for ‘at-risk’ drinkers) in general practices with the current practice scenario (no SBI) in the Netherlands. We used the RIVM Chronic Disease Model (CDM) to extrapolate from decreased alcohol consumption to effects on health care costs and Quality Adjusted Life Years (QALYs) gained. Probabilistic sensitivity analysis was employed to study the effect of uncertainty in the model parameters. In total, 56,000 QALYs were gained at an additional cost of €298,000,000 due to providing alcohol SBI in the target population, resulting in a cost-effectiveness ratio of €5,400 per QALY gained.

Conclusion

Prevention of excessive alcohol use by implementing SBI for excessive alcohol use in primary care settings appears to be cost-effective.     

MicroRNAs in the tumor endothelium: Novel controls on the angioregulatory switchboard

Tumor angiogenesis facilitates tumor metastasis and allows malignant tissues to grow beyond a diffusion limited size. It is a complex process that requires endothelial cells to execute specific steps during different phases. miRNAs are small non-coding RNAs that act as molecular switches to redirect the expression profile of a cell. Evidence is emerging that miRNAs are important players in endothelial cell biology and tumor angiogenesis. In this review we summarize the available data of miRNA expression in the endothelium. In addition, we describe the current knowledge regarding the function of miRNAs in endothelial cell biology. Finally, we discuss the potential applications of miRNA based treatment strategies in angiostatic cancer therapy.     

Munc18 and Munc13 regulate early neurite outgrowth

Background information. During development, growth cones of outgrowing neurons express proteins involved in vesicular secretion, such as SNARE (soluble N‐ethylmaleimide‐sensitive fusion protein‐attachment protein receptor) proteins, Munc13 and Munc18. Vesicles are known to fuse in growth cones prior to synapse formation, which may contribute to outgrowth. Results. We tested this possibility in dissociated cell cultures and organotypic slice cultures of two release‐deficient mice (Munc18‐1 null and Munc13‐1/2 double null). Both types of release‐deficient neurons have a decreased outgrowth speed and therefore have a smaller total neurite length during early development [DIV1–4 (day in vitro 1–4)]. In addition, more filopodia per growth cone were observed in Munc18‐1 null, but not WT (wild‐type) or Munc13‐1/2 double null neurons. The smaller total neurite length during early development was no longer observed after synaptogenesis (DIV14–23). Conclusion. These data suggest that the inability of vesicle fusion in the growth cone affects outgrowth during the initial phases when outgrowth speed is high, but not during/after synaptogenesis. Overall, the outgrowth speed is probably not rate‐limiting during neuronal network formation, at least in vitro. In addition, Munc18, but not Munc13, regulates growth cone filopodia, potentially via its previously observed effect on filamentous actin.     

Memory in the making: localized brain activation related to song learning in young songbirds

Songbird males learn to sing their songs from an adult ‘tutor’ early in life, much like human infants learn to speak. Similar to humans, in the songbird brain there are separate neural substrates for vocal production and for auditory memory. In adult songbirds, the caudal pallium, the avian equivalent of the auditory association cortex, has been proposed to contain the neural substrate of tutor song memory, while the song system is involved in song production as well as sensorimotor learning. If this hypothesis is correct, there should be neuronal activation in the caudal pallium, and not in the song system, while the young bird is hearing the tutor song. We found increased song-induced molecular neuronal activation, measured as the expression of an immediate early gene, in the caudal pallium of juvenile zebra finch males that were in the process of learning to sing their songs. No such activation was found in the song system. Molecular neuronal activation was significantly greater in response to tutor song than to novel song or silence in the medial part of the caudomedial nidopallium (NCM). In the caudomedial mesopallium, there was significantly greater molecular neuronal activation in response to tutor song than to silence. In addition, in the NCM there was a significant positive correlation between spontaneous molecular neuronal activation and the strength of song learning during sleep. These results suggest that the caudal pallium contains the neural substrate for tutor song memory, which is activated during sleep when the young bird is in the process of learning its song. The findings provide insight into the formation of auditory memories that guide vocal production learning, a process fundamental for human speech acquisition.     

The age of immigration of the vertebrate faunas found at Gargano (Apulia,Italy) and Scontrone (l’Aquila,Italy)

Recently a discussion is taking place about the Scontrone (l’Aquila) and Gargano (Apulia, Italy) mammal faunas and the age of their immigration. Mazza and Rustioni (2008) dated the Scontrone mammal fossils as Tortonian on the basis of their position in the Lithothamnium Limestone and came to the conclusion that some elements of the Scontrone and Gargano faunas must have colonised the area in Oligocene or Early Miocene times. Van den Hoek Ostende et al. (2009) disagreed with this interpretation and suggested a Late Miocene (10 Ma) age for the time of immigration. We think the arguments to place Scontrone in the Tortonian are not convincing. An analysis of the potential ancestors of each of the Gargano faunal components shows that a Messinian age for the immigration is fully compatible with the distribution of these ancestors in the European Miocene.     

A novel 7.4 kb mitochondrial deletion in a patient with congenital progressive external ophthalmoplegia, muscle weakness and mental retardation.

We present a patient with external ophthalmoplegia, bilateral ptosis, progressive muscle weakness with "ragged-red fibres" and mental retardation. Mitochondrial DNA analysis by Southern blot revealed heteroplasmy in muscle for a 7.4 kb deletion. In white blood cells, the deletion was only detectable by PCR. There was no evidence for duplications, nor for multiple deletions in the proband or siblings. PCR analysis did not reveal the presence of a mitochondrial DNA defect in the parents and siblings. Thus, there is no experimental support for a maternally inherited mitochondrial DNA deletion. We consider this a sporadic case with a de novo deletion. Diabetes and complaints of fatigue, also seen in this family, are probably coincidental. Mental retardation has been reported occasionally in patients with mitochondrial deletions, but is not common.     

Carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase-deficiency)

The carbohydrate-deficient glycoprotein or CDG syndromes (OMIM 212065) are a recently delineated group of genetic, multisystem diseases with variable dysmorphic features. The known CDG syndromes are characterized by a partial deficiency of the N-linked glycans of secretory glycoproteins, lysosomal enzymes, and probably also membranous glycoproteins. Due to the deficiency of terminal N-acetylneuraminic acid or sialic acid, the glycan changes can be observed in serum transferrin or other glycoproteins using isoelectrofocusing with immunofixation as the most widely used diagnostic technique. Most patients show a serum sialotransferrin pattern characterized by increased di- and asialotransferrin bands (type I pattern). The majority of patients with type I are phosphomannomutase deficient (type IA), while in a few other patients, deficiencies of phosphomannose isomerase (type IB) or endoplasmic reticulum glucosyltransferase (type IC) have been demonstrated. This review is an update on CDG syndrome type IA.