Statin therapy and stroke prevention: what was known, what is new and what is next?

PURPOSE OF REVIEW: Randomized trials have shown that statins may reduce the risk of primary stroke. There is no evidence however that statins can reduce recurrent stroke incidence. RECENT FINDINGS: In the SPARCL trial, patients with a recent stroke or transient ischemic attack randomized to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke, and a 35% reduction in major coronary events compared with placebo. This was obtained despite 25% of the placebo arm patients receiving a commercially-available statin outside of the trial. Post-hoc analysis used blinded LDL-cholesterol measurements as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-cholesterol (the group adherent to placebo or not taking a statin), the group with over 50% reduction in LDL-cholesterol had a significant 31% reduction in stroke. The next step is to define whether achieving LDL-cholesterol below 70 mg/dl is better than a standard dose of statin (LDL around 100-110 mg/dl) in the secondary prevention of stroke. SUMMARY: Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-cholesterol lowering.     

Disruptive selection and then what?

Disruptive selection occurs when extreme phenotypes have a fitness advantage over more intermediate phenotypes. The phenomenon is particularly interesting when selection keeps a population in a disruptive regime. This can lead to increased phenotypic variation while disruptive selection itself is diminished or eliminated. Here, we review processes that increase phenotypic variation in response to disruptive selection and discuss some of the possible outcomes, such as sympatric species pairs, sexual dimorphisms, phenotypic plasticity and altered community assemblages. We also identify factors influencing the likelihoods of these different outcomes.     

Actin in the nucleus: what form and what for?

Actin is an abundant protein in most nonmuscle cells. It has often been observed in isolated nuclei, yet cytoplasmic contamination was of course initially regarded as the most plausible origin. Numerous studies on nuclear actin appeared in the 1970s and 1980s, but the picture remained rather muddy. The viewpoint at that time was that actin-shown to move freely between cytoplasm and nucleus-was a mere "thermodynamic wanderer," transiently occupying the nucleus. More recently, evidence has been mounting that actin's presence in the nucleus is not simply governed by the laws of diffusion. The same holds true for the finding of various actin-related proteins in the nucleus, and the case for nuclear myosin, specifically myosin I, is now quite convincing. Moreover, the first intimations of functional roles of nuclear actin are now emerging. Here we examine the overall subject from cell biological and chemical perspectives. The major issue is no longer the presence of actin in the nucleus but rather its supramolecular organization, intranuclear locations, and, of course, functions. These issues interface with recent findings that reveal a surprisingly diverse repertoire of actin conformations and oligomer and polymer forms beyond monomeric G-actin and polymeric F-actin. We present ideas for advancing the nuclear actin field and call for a renewed attack on this major problem in cell biology.     

Atrial fibrillation and what else?

Netherlands Heart Journal -     

Treatment with anthelminthics during pregnancy: what gains and what risks for the mother and child?

In 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered.     

Statin pharmacogenomics: what have we learned, and what remains unanswered?

PURPOSE OF REVIEW: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary heart disease. Response to treatment varies considerably from person to person; however, inherited traits (genetic variability) may play a central role in this inter-individual variation. The purpose of this review is to summarize recent progress in the research for exploring genetic determinants of clinical efficacy and safety of statin therapy. RECENT FINDINGS: In addition to 41 previous studies of 19 genes, the results of 17 pharmacogenomic studies investigating the relationship between common genetic variants and response to statin therapy in terms of lipid responses, clinical outcomes, and adverse events have been reported since January 2004 - 15 candidate genes related to pharmacodynamics and three to pharmacokinetics of statins. These reported data suggest that genetic variations influencing intestinal cholesterol absorption, cholesterol production, and lipoprotein catabolism may all play a role in modulating responsiveness, as well as genes involved in drug metabolism of statins. They also suggest that combined analysis of multiple variants in several genes, all of which have possible functional relations, is more likely to give significant results, especially when being performed with a larger number of participants. SUMMARY: Pharmacogenomic studies of statin therapy will provide a better picture as to who is most likely and least likely to benefit from treatment, which results in more individualized management of coronary artery disease.     

Studying molecular motor-based cargo transport: what is real and what is noise?

Noise is a major problem in analyzing tracking data of cargos moved by molecular motors. We use Bayesian statistics to incorporate what is known about the noise in parsing the trajectory of a cargo into a series of constant velocity segments. Tracks with just noise and no underlying motion are fit with constant velocity segments to produce a calibration curve of fit quality versus average segment duration. Fits to tracks of moving cargos are compared to the calibration curves with similar noise. The fit with the optimum number of constant velocity states has the least number of segments needed to match the fit quality of the calibration curve. We have tested this approach using tracks with known underlying motion generated by computer simulations and with a specially designed in vitro experiment. We present the results of using this parsing approach to analyze transport of lipid droplets in Drosophila embryos.     

Pain and distress: what really matters?

Federal regulations mandate the minimization of both pain and distress in laboratory animals. That no clear definition exists for 'distress' complicates its recognition, quantification, and alleviation. The author argues that IACUCs and investigators should shift their focus from pain to distress, and that in doing so both problems will be better dealt with. She discusses criteria for defining 'significant' distress, and offers suggestions for the conduct of studies to determine levels of distress.     

Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them?

The development of nucleoside phosphorothioates is described in its historical context. Examples of the interaction of phosphorothioate groups, present either in oligodeoxynucleotides or in DNA, with nucleases are presented. The structural features responsible for the resistance of the phosphorothioates toward degradation by nucleases are discussed, as are the possible reasons for the high-affinity interaction of phosphorothioate oligodeoxynucleotides with certain proteins.     

Independent component analysis of functional MRI: what is signal and what is noise?

Many sources of fluctuation contribute to the functional magnetic resonance imaging (fMRI) signal, complicating attempts to infer those changes that are truly related to brain activation. Unlike methods of analysis of fMRI data that test the time course of each voxel against a hypothesized waveform, data-driven methods, such as independent component analysis and clustering, attempt to find common features within the data. This exploratory approach can be revealing when the brain activation is difficult to predict beforehand, such as with complex stimuli and internal shifts of activation that are not time-locked to an easily specified sensory or motor event. These methods can be further improved by incorporating prior knowledge regarding the temporal and spatial extent of brain activation.     

Safe and efficacious probiotics: what are they?

Each year, >20 billion doses of probiotics are used by healthy people and by those diagnosed with a range of medical conditions. Compared to many pharmaceutical agents, probiotics are well tolerated and extremely safe, and serious adverse effects rarely occur. Nevertheless, as many new researchers enter the field and companies launch "probiotic" products, it is essential that standards are set for naming a product "probiotic" to show that it meets an acceptable level of safety and efficacy, and to understand the strengths and limitations of its activity. In this Opinion article, recommendations are made based upon the current understanding of scientific, clinical and regulatory issues, with a special focus on safety.     

Autophagy and apoptosis: what is the connection?

The therapeutic potential of autophagy for the treatment cancer and other diseases is beset by paradoxes stemming from the complexity of the interactions between the apoptotic and autophagic machinery. The simplest question of how autophagy acts as both a protector and executioner of cell death remains the subject of substantial controversy. Elucidating the molecular interactions between the processes will help us understand how autophagy can modulate cell death, whether autophagy is truly a cell death mechanism, and how these functions are regulated. We suggest that, despite many connections between autophagy and apoptosis, a strong causal relationship wherein one process controls the other, has not been demonstrated adequately. Knowing when and how to modulate autophagy therapeutically depends on understanding these connections.     

Transgenesis and yield: what are our targets?

Plant metabolic engineering has been used to generate a wide range of transgenic lines in which specific metabolic steps have been targeted. Attempts to increase yield of some agronomically important crops using this approach have highlighted the inherent complexities of modulating plant metabolism. In light of the recent findings by Regierer et al. this article addresses the major challenges faced with respect to enhancing yield through transgenesis.