Prospective cohort studies on risk factors for cardiovascular events in systemic lupus erythematosus: a major challenge

Cardiovascular disease (CVD) has been identified as a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). The etiology of premature CVD in SLE is supposed to have many factors, including traditional coronary artery disease (CAD) risk factors, antiphospholipid antibodies, and metabolic and inflammatory factors. Despite the overwhelming interest in CVD in SLE research, prospective studies evaluating risk factors for hard endpoints (that is, cardiovascular events) are relatively scarce. The article by Gustafsson and colleagues suggests that prothrombotic factors play an important role in SLE-related CVD and that the influence of traditional CAD risk factors might be limited.     

A kernelisation approach for multiple d-Hitting Set and its application in optimal multi-drug therapeutic combinations

Therapies consisting of a combination of agents are an attractive proposition, especially in the context of diseases such as cancer, which can manifest with a variety of tumor types in a single case. However uncovering usable drug combinations is expensive both financially and temporally. By employing computational methods to identify candidate combinations with a greater likelihood of success we can avoid these problems, even when the amount of data is prohibitively large. Hitting Set is a combinatorial problem that has useful application across many fields, however as it is NP-complete it is traditionally considered hard to solve exactly. We introduce a more general version of the problem (α,β,d)-Hitting Set, which allows more precise control over how and what the hitting set targets. Employing the framework of Parameterized Complexity we show that despite being NP-complete, the (α,β,d)-Hitting Set problem is fixed-parameter tractable with a kernel of size O(αdk(d)) when we parameterize by the size k of the hitting set and the maximum number α of the minimum number of hits, and taking the maximum degree d of the target sets as a constant. We demonstrate the application of this problem to multiple drug selection for cancer therapy, showing the flexibility of the problem in tailoring such drug sets. The fixed-parameter tractability result indicates that for low values of the parameters the problem can be solved quickly using exact methods. We also demonstrate that the problem is indeed practical, with computation times on the order of 5 seconds, as compared to previous Hitting Set applications using the same dataset which exhibited times on the order of 1 day, even with relatively relaxed notions for what constitutes a low value for the parameters. Furthermore the existence of a kernelization for (α,β,d)-Hitting Set indicates that the problem is readily scalable to large datasets.     

Towards an AIDS vaccine: the role of nonhuman primates

Over the last 10 years, about 20 human immunodeficiency virus (HIV) vaccine candidates have been tried in humans, with disappointing results as gauged by limited immune responses or protection against infection. These difficulties suggest that a new strategy is needed to test systematically new vaccine candidates. That opportunity is now afforded by nonhuman primate models with SIV, which have been shown to provide an excellent mirror of HIV infection in humans. The recent introduction of SHIVs, chimeric viruses that carry the HIV envelope and are able to infect and cause AIDS in monkeys, also has added an important additional research tool. These models can be used to address a series of questions, including the following: (1) Can protection be provided by partial immunity or is sterilizing immunity required? (2) What are the immune parameters that best predict protection against a potentially pathogenic challenge? (3) What role does mucosal immunity play and can it be induced by practical modes of immunization? (4) Can an attenuated virus be selected that is both protective and safe? An orderly strategy for the evaluation of vaccine candidates could be adopted that would involve several phases: (a) the selection of a limited set of challenge models, ranging from very severe to mild and requiring consideration of primate species, age, route of infection, and challenge viruses; (b) the assessment of candidate vaccines using comparable virus challenges; and (c) accelerated testing in humans of any candidate vaccines that have met a 'proof of efficacy' in primates.     

Polygalacturonase inhibiting protein in plant cell walls

Polygalacturonase inhibiting protein (PGIP) is localized in plant cell walls and plays an important role both in pectic substance metabolism and in prevention of the penetration of phytopathogenic microorganisms. Apparently, PGIP is responsible for the specificity of cell--cell interactions during pollination or inoculation by fungi nonpathogenic for the particular plant. PGIPs from different plants share a basic common structure. They are rather thermostable glycoproteins enriched with leucine and contain about 20% carbohydrates; the molecular weight varies between 37-54 kD. The synthesis of PGIP is encoded by one gene, and its expression is stimulated by injury and fungal infection. The resistance of plant tissues to infection frequently correlates with PGIP expression and with inhibiting action on fungal PG. Thus, PGIP is believed to be useful for gene engineering to obtain transgenic plants resistant to fungal infection or retaining commercial value during storage.     

An examination of the population genetics of Laminaria and other brown algae in the laminariales using starch gel electrophoresis

While some investigators have attempted to use isozyme electrophoresis to gain information on the genetics of brown algae, most have reported unsatisfactory results. Through exhaustive screening and modification of sample preparation techniques, gel and tray buffers systems, plus staining recipes, we have developed procedures that consistently provide scorable bands for over 20 enzyme systems in several laminarian algae. We have used our procedures to examine geographically diverse populations of Laminaria saccharina and L. longicruris, as well as L. digitata, L. groenlandica, Agarum cribrosum, Alaria esculenta, Chorda tomentosa, and Macrocystis pyrifera. Overall, these kelp species seem to have an extremely low degree of enzyme solymorphism, both within and between populations. While some rare alleles occurred in several enzyme systems, only 3–5 loci were found to be polymorphic. Our results are consistent with the few reported studies that have used molecular genetic techniques to look at the intraspecific variability of laminarian algae. We suggest that at the species level the Laminariales, and perhaps other groups of brown algae, are genetically extremely conservative as compared to other divisions of plants. We further suggest that isozyme electrophoresis provides a quick and useful tool for algal population genetic studies.     

Very long-lived messenger RNA in ovaries of Xenopus laevis

It is possible to label with radioactivity newly synthesized ovarian RNA after intraperitoneal injection of [³H]guanosine and [³H]uridine into immature Xenopus laevis, if ovaries in which only previtellogenic stage 1 oocytes are present. Following the amount of radioactivity in the ovarian pool of acid-soluble precursors indicates a complete clearance of acid-soluble radioactivity within 15–20 days after injection. Incorporation of radioactivity into total RNA (which is almost exclusively 4 and 5S RNAs at this stage) and poly(A)⁺ RNA ceases between 15 and 20 days after injection, but the total amount of radioactivity in these RNA fractions does not decline appreciably over the next 18 months. During this time, the ovary grows and develops since stage 6 oocytes eventually appear and there is a 10- to 20-fold increase in total RNA content, which changes in composition from almost exclusively (95%) 4 and 5S RNAs to mainly (75%) 18 and 28S RNAs. Thus, despite continued growth and development, radioactive RNA molecules synthesized during previtellogenesis survive for lengths of time commensurate with the length of oogenesis (1–2 years). Although very limited (<7%) reincorporation of radioactivity into RNA is detected, it cannot alone account for the stability of the label in poly(A)⁺ RNA. These results are interpreted as indicative of synthesis during previtellogenesis of tRNA, 5SrRNA, and messenger RNA molecules which are very long-lived.     

Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis

Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease. These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454 incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms, tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness, type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction. Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation but differs with respect to disease course.