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.     

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.     

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.     

What is a cladogram and what is not?

The origins and meanings of “cladogram” are reviewed. Traditionally, “cladogram” has been defined as a graphical representation of an empirical hypothesis of relationships among taxa, based on evidence from synapomorphies alone. Disturbingly, numerous recent authors treat “cladogram” as synonymous with “dendrogram” and do not appreciate the particular methodological connotations of the former term. This is lamented.     

Venous ulcer: what is new?

The pathophysiology of venous dermal abnormality in chronic venous ulcers is reflective of a complex interplay that involves sustained venous hypertension, inflammation, changes in the microcirculation, cytokine and matrix metalloproteinase activation, and altered cellular function. Red blood cells and macromolecules extravasate into the interstitium and activate endothelial cells. Endothelial expression of specific adhesion molecules recruits leukocytes and causes diapedesis of these cells into the dermal microvasculature, promoting an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues, initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency and ulcer formation. The mainstay of therapy in venous ulcer abnormality is correction of the underlying venous hypertension through compression therapy and/or surgery. Understanding the science involved in the pathophysiology of venous ulcer formation has led to the development of adjunctive treatment directed at the dysregulated molecular pathways. Randomized clinical trials are critical for determining the most effective evidence-based treatments for venous ulcer, and this review discusses important trials that have had a significant impact on venous ulcer healing. In addition, the authors have included subsections referred to as "Translational Implications for Therapy" in the basic science sections of the review to help bridge the basic science knowledge with clinical applications that may help to modulate the molecular abnormalities in the pathophysiologic cascade leading to venous ulcers.     

If neuroimaging is the answer,what is the question?

It is unclear that we will come to a better understanding of mental processes simply by observing which neural loci are activated while subjects perform a task. Rather, I suggest here that it is better to come armed with a question that directs one to design tasks in ways that take advantage of the strengths of neuroimaging techniques (particularly positron emission tomography and functional magnetic resonance imaging). Here I develop a taxonomy of types of questions that can be easily addressed by such techniques. The first class of questions focuses on how information processing is implemented in the brain; these questions can be posed at a very coarse scale, focusing on the entire system that confers a particular ability, or at increasingly more specific scales, ultimately focusing on individual structures or processes. The second class of questions focuses on specifying when particular processes and structures are invoked; these questions focus on how one can use patterns of activation to infer that specific processes and structures were invoked, and on how processing changes in different circumstances. The use of neuroimaging to address these questions is illustrated with results from experiments on visual cognition, and caveats regarding the logic of inference in each case are noted. Finally, the necessary interplay between neuroimaging and behavioural studies is stressed.     

What is signal and what is noise in the brain?

The response of a cortical neuron to a stimulus can show a very large variability when repeatedly stimulated by exactly the same stimulus. This has been quantified in terms of inter-spike-interval (ISI) statistics by several researchers (e.g., [Softky, W., Koch, C., 1993. The highly irregular firing of cortical cells is inconsistent with temporal integration of random EPSPs. J. Neurosci. 13(1), 334-350.]). The common view is that this variability reflects noisy information processing based on redundant representation in large neuron populations. This view has been challenged by the idea that the apparent noise inherent in brain activity that is not strictly related or temporally coupled to the experiment could be functionally significant. In this work we examine the ISI statistics and discuss these views in a recently published model of interacting cortical areas [Knoblauch, A., Palm, G., 2002. Scene segmentation by spike synchronization in reciprocally connected visual areas. I. Local effects of cortical feedback. Biol. Cybernet. 87(3), 151-167.]. From the results of further single neuron simulations we can isolate temporally modulated synaptic input as a main contributor for high ISI variability in our model and possibly in real neurons. In contrast to alternative mechanisms, our model suggests a function of the temporal modulations for short-term binding and segmentation of figures from background. Moreover, we show that temporally modulated inputs lead to ISI statistics which fit better to the neurophysiological data than alternative mechanisms.     

Coral diseases: what is really known?

Reports of new and emerging coral diseases have proliferated in recent years. Such coral diseases are often cited as contributing to coral reef decline. Many of these diseases, however, have been described solely on the basis of field characteristics, and in some instances there is disagreement as to whether an observed coral condition is actually a disease. A disease pathogen has been identified for only three coral diseases, and for only two of these has the pathogen been shown (in the laboratory) to be the disease agent. In one case, the same disease name has been used for several widely varying coral syndromes, whereas in another multiple disease names have been applied to symptoms that may be caused by a single disease. Despite the current confusion, rapid progress is being made.     

Chimeric restriction enzymes: what is next?

Chimeric restriction enzymes are a novel class of engineered nucleases in which the non-specific DNA cleavage domain of Fokl (a type IIS restriction endonuclease) is fused to other DNA-binding motifs. The latter include the three common eukaryotic DNA-binding motifs, namely the helix-turn-helix motif, the zinc finger motif and the basic helix-loop-helix protein containing a leucine zipper motif. Such chimeric nucleases have been shown to make specific cuts in vitro very close to the expected recognition sequences. The most important chimeric nucleases are those based on zinc finger DNA-binding proteins because of their modular structure. Recently, one such chimeric nuclease, Zif-QQR-F(N) was shown to find and cleave its target in vivo. This was tested by microinjection of DNA substrates and the enzyme into frog oocytes (Carroll et al., 1999). The injected enzyme made site-specific double-strand breaks in the targets even after assembly of the DNA into chromatin. In addition, this cleavage activated the target molecules for efficient homologous recombination. Since the recognition specificity of zinc fingers can be manipulated experimentally, chimeric nucleases could be engineered so as to target a specific site within a genome. The availability of such engineered chimeric restriction enzymes should make it feasible to do genome engineering, also commonly referred to as gene therapy.     

Early puberty: what is normal and when is treatment indicated?

Girls and boys who enter puberty before 8 and 9 years of age, respectively (corresponding to about -3 SDS), are arbitrarily considered to need referral for endocrine investigation. A recent report from the Lawson Wilkins Pediatric Endocrine Society suggested that the limit for investigation of girls and boys should be lowered to 7 and 8 years, respectively. For African-American girls, 6 years is the suggested age. This recommendation has been criticized. Although short stature is a common end result of precocious puberty, short- and long-term psychological symptoms may be more important, since several studies have indicated psychopathology in this patient group. Whether this can be prevented by gonadotropin releasing hormone agonist treatment remains to be shown. This review will highlight the psychological aspects of early puberty. In short, aspects other than height should also be evaluated when considering treatment of the early maturing child.