What have we learnt about microarray analyses of atherogenesis?

PURPOSE OF REVIEW: This review covers recent developments in microarray studies in the field of atherogenesis research. RECENT FINDINGS: During the past year microarrays have been applied to the analysis of pathogenic mechanisms of several atherosclerosis risk factors, including ageing, hypertension, obesity, and cytomegalovirus infection. In addition, gene expression patterns during the development of in-stent restenosis have been examined. Several studies have also explored the pleiotropic effects of statin therapy. As a technical improvement, the combination of laser microdissection with microarrays in human samples has been reported. SUMMARY: Microarray analyses have given important new information about atherogenesis. It is anticipated that microarray studies will significantly contribute to further discoveries in the field.     

Screening with mammography organized by family physicians teams: what have we learnt?

The mammography, recommended as standard method for screening on breast cancer, can reveal suspicious lesions early enough to anable cancer elimination in entirely. Experience with women of the target population, 50-69 years old, included in the mass screening programs, show the reduction in the specific mortality by 30%. One of the main problem in organizing the preventive programs is how to increase responsiveness of subjects to screening. In the study, based on the large sample of over 1000 of subjects and 20 family medicine practices, included in the investigation, we showed that it is possible, by a pro-active involvement of family physicians teams and intensive educational and motivational activities, to achieve high level of over 80% of responsiveness to mammography screening. Analysis of the reasons of nonresponsiveness can contribute to better understanding of the mental processes included in a self-decision making. This, as the final aim, can help family physicians in their efforts to overcome many hidden barriers which obstruct their patients to accept the mammography screening.     

What have we learnt from SARS?

With outbreaks of infectious disease emerging from animal sources, we have learnt to expect the unexpected. We were, and are, expecting a new influenza A pandemic, but no one predicted the emergence of an unknown coronavirus (CoV) as a deadly human pathogen. Thanks to the preparedness of the international network of influenza researchers and laboratories, the cause of severe acute respiratory syndrome (SARS) was rapidly identified, but there is no complacency over the global or local management of the epidemic in terms of public health logistics. The human population was lucky that only a small proportion of infected persons proved to be highly infectious to others, and that they did not become so before they felt ill. These were the features that helped to make the outbreak containable. The next outbreak of another kind of transmissible disease may well be quite different.     

Convergence and parallelism reconsidered: what have we learned about the genetics of adaptation?

Biologists often distinguish 'convergent' from 'parallel' evolution. This distinction usually assumes that when a given phenotype evolves, the underlying genetic mechanisms are different in distantly related species (convergent) but similar in closely related species (parallel). However, several examples show that the same phenotype might evolve among populations within a species by changes in different genes. Conversely, similar phenotypes might evolve in distantly related species by changes in the same gene. We thus argue that the distinction between 'convergent' and 'parallel' evolution is a false dichotomy, at best representing ends of a continuum. We can simplify our vocabulary; all instances of the independent evolution of a given phenotype can be described with a single term - convergent.     

Testing methods in species distribution modelling using virtual species: what have we learnt and what are we missing?

Species distribution models (SDMs) have become one of the major predictive tools in ecology. However, multiple methodological choices are required during the modelling process, some of which may have a large impact on forecasting results. In this context, virtual species, i.e. the use of simulations involving a fictitious species for which we have perfect knowledge of its occurrence–environment relationships and other relevant characteristics, have become increasingly popular to test SDMs. This approach provides for a simple virtual ecologist framework under which to test model properties, as well as the effects of the different methodological choices, and allows teasing out the effects of targeted factors with great certainty. This simplification is therefore very useful in setting up modelling standards and best practice principles. As a result, numerous virtual species studies have been published over the last decade. The topics covered include differences in performance between statistical models, effects of sample size, choice of threshold values, methods to generate pseudo‐absences for presence‐only data, among many others. These simulations have therefore already made a great contribution to setting best modelling practices in SDMs. Recent software developments have greatly facilitated the simulation of virtual species, with at least three different packages published to that effect. However, the simulation procedure has not been homogeneous, which introduces some subtleties in the interpretation of results, as well as differences across simulation packages. Here we 1) review the main contributions of the virtual species approach in the SDM literature; 2) compare the major virtual species simulation approaches and software packages; and 3) propose a set of recommendations for best simulation practices in future virtual species studies in the context of SDMs.     

Genetics of rheumatoid arthritis: what have we learned?

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5–1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70–74 of the DRβ1 chain are associated with the disease. The HLA molecules carrying these “shared epitope” sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA.     

Marine phage genomics: what have we learned?

Marine phages are the most abundant and diverse form of life on the planet, and their genomes have been described as the largest untapped reservoir of genomic information. To date, however, the complete genome sequences of only 17 marine phage are known. Nevertheless, these genomes have revealed some interesting features, including the presence of photosynthetic genes in cyanophage and common patterns of genomic organization. Intriguing findings are also being made from studies of the uncultivated marine viral community genome ('metavirome'). The greatest challenge in interpreting the biology of these phages, and for making comparisons with their terrestrial counterparts, is the high proportion of unidentifiable open reading frames (approximately 60%). Future studies are likely to focus on sequencing more marine phage genomes from disparate hosts and diverse environments and on further basic studies of the biology of existing marine phages.     

Timeline: AIDS pathogenesis: what have two decades of HIV research taught us?

22 years ago, the first cases of an acquired immunodeficiency syndrome afflicting young, homosexual American men were reported, heralding what we now know to be the beginning of the HIV epidemic. Since then, billions of US dollars have been invested in HIV research in the hope of gaining a better understanding of this infection and how to prevent and treat it. What are the landmarks in HIV research over the past two decades, and what questions still remain to be answered? What has the intense study of HIV infection taught us about other virus infections and how our immune system responds to them?     

Insecticide resistance in the mosquito Culex pipiens: what have we learned about adaptation?

Resistance to organophosphate (OP) insecticide in the mosquito Culex pipiens has been studied for ca. 30 years. This example of micro-evolution has been thoroughly investigated as an opportunity to assess precisely both the new adapted phenotypes and the associated genetic changes. A notable feature is that OP resistance is achieved with few genes, and these genes have generally large effects. The molecular events generating such resistance genes are complex (e.g., gene amplification, gene regulation) potentially explaining their low frequency of de novo occurrence. In contrast, migration is a frequent event, including passive transportation between distant populations. This generates a complex interaction between mutations and migration, and promotes competition among resistance alleles. When the precise physiological action of each gene product is rather well known, it is possible to understand the dominance level or the type of epistasis observed. It is however difficult to predict a priori how resistance genes will interact, and it is too early to state whether or not this will be ever possible. These resistance genes are costly, and the cost is variable among them. It is usually believed that the initial fitness cost would gradually decrease due to subsequent mutations with a modifier effect. In the present example, a particular modifier occurred (a gene duplication) at one resistance locus, whereas at the other one reduction of cost is driven by allele replacement and apparently not by selection of modifiers.     

What have we learned from clinical trials in primary Sj?gren's syndrome about pathogenesis?

In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sj?gren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS.     

Fossils of parasites: what can the fossil record tell us about the evolution of parasitism?

Parasites are common in many ecosystems, yet because of their nature, they do not fossilise readily and are very rare in the geological record. This makes it challenging to study the evolutionary transition that led to the evolution of parasitism in different taxa. Most studies on the evolution of parasites are based on phylogenies of extant species that were constructed based on morphological and molecular data, but they give us an incomplete picture and offer little information on many important details of parasite–host interactions. The lack of fossil parasites also means we know very little about the roles that parasites played in ecosystems of the past even though it is known that parasites have significant influences on many ecosystems. The goal of this review is to bring attention to known fossils of parasites and parasitism, and provide a conceptual framework for how research on fossil parasites can develop in the future. Despite their rarity, there are some fossil parasites which have been described from different geological eras. These fossils include the free‐living stage of parasites, parasites which became fossilised with their hosts, parasite eggs and propagules in coprolites, and traces of pathology inflicted by parasites on the host's body. Judging from the fossil record, while there were some parasite–host relationships which no longer exist in the present day, many parasite taxa which are known from the fossil record seem to have remained relatively unchanged in their general morphology and their patterns of host association over tens or even hundreds of millions of years. It also appears that major evolutionary and ecological transitions throughout the history of life on Earth coincided with the appearance of certain parasite taxa, as the appearance of new host groups also provided new niches for potential parasites. As such, fossil parasites can provide additional data regarding the ecology of their extinct hosts, since many parasites have specific life cycles and transmission modes which reflect certain aspects of the host's ecology. The study of fossil parasites can be conducted using existing techniques in palaeontology and palaeoecology, and microscopic examination of potential material such as coprolites may uncover more fossil evidence of parasitism. However, I also urge caution when interpreting fossils as examples of parasites or parasitism‐induced traces. I point out a number of cases where parasitism has been spuriously attributed to some fossil specimens which, upon re‐examination, display traits which are just as (if not more) likely to be found in free‐living taxa. The study of parasite fossils can provide a more complete picture of the ecosystems and evolution of life throughout Earth's history.     

Clamp techniques in paediatrics: what have we learned?

The marked increase in conditions associated with insulin resistance in youth, including obesity, polycystic ovary syndrome, type 2 diabetes mellitus etc., has prompted the need to assess insulin sensitivity in this age group. Even though insulin resistance plays an important role in disorders of glucose metabolism and other pathological conditions, both insulin sensitivity and insulin secretion should be determined for a comprehensive evaluation of glucose homeostasis disorders. Insulin sensitivity and secretion are intricately coupled with a delicate feedback mechanism governing their relationship. This article will delineate our paediatric experience with the clamp technique, the hyperinsulinaemic-euglycaemic clamp in assessing in vivo insulin sensitivity, and the hyperglycaemic clamp in assessing insulin secretion.     

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.