Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score

Introduction  

Frequent assessments of rheumatoid arthritis (RA) disease activity allow timely adaptation of therapy, which is essential in preventing disease progression. However, values of acute phase reactants (APRs) are needed to calculate current composite activity indices, such as the Disease Activity Score (DAS)28, the DAS28-CRP (i.e. the DAS28 using C-reactive protein instead of erythrocyte sedimentation rate) and the Simplified Disease Activity Index (SDAI). We hypothesized that APRs make limited contribution to the SDAI, and that an SDAI-modification eliminating APRs – termed the Clinical Disease Activity Index (CDAI; i.e. the sum of tender and swollen joint counts [28 joints] and patient and physician global assessments [in cm]) – would have comparable validity in clinical cohorts.     

Synthesis and biological evaluation of conformationally restricted and nucleobase-modified analogs of the anticancer compound 3'-C-ethynylcytidine (ECyd)

A series of conformationally restricted and nucleobase-modified analogs of the anticancer compound 3'-C-ethynylcytidine (ECyd) and its uracil analog (EUrd) have been synthesized. While none of the conformationally restricted analogs displayed anticancer activity, 5-iodo-EUrd and 5-bromo-EUrd displayed potent anticancer activity with IC50 values of 35 nM and 0. 73 microM.     

Aspects of early arthritis. Traditional DMARD therapy: is it sufficient?

There is increasing evidence for beneficial effects of early DMARD (disease-modifying antirheumatic drug) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drugs or combinations should be given as initial treatments. Recent studies have focused on the benefits of various strategies in which treatments were tailored to achieve low levels of disease activity, as assessed using validated response criteria. These studies demonstrated superiority of 'aggressive' over 'conventional' approaches. Whether the inclusion of tumour necrosis factor antagonists or other biologic targeted therapies in such strategies confers additional benefits in terms of improved long-term outcomes must be clarified by further studies. Assessment of risks in the individual patient, allowing individual 'tailoring' of the initial treatment, would be desirable.     

Population genetics of the native caribou (Rangifer tarandus groenlandicus) and the semi-domestic reindeer (Rangifer tarandus tarandus) in Southwestern Greenland: Evidence of introgression

Over the past centuries the native caribou ofWest Greenland has gone through extensive population size fluctuations, with reductionsas great as 90% in less than 20 years.Norwegian semi-domestic reindeer wereintroduced to the Nuuk area in 1952 because ofthe small number of caribou in Greenland.Although the reindeer and caribou wereinitially kept separated, mixing has occurredsince the 1970's. We investigated the genotypicstructure of caribou and reindeer in South-westGreenland, using five polymorphicmicrosatellite markers isolated from cattle,sheep, goat and red deer. A total of ninetysamples were collected, which included samplesfrom caribou of four different regions andsamples from two different reindeer herds.Based on the genetic variation of the fivemarkers, our results shows that the caribou andthe reindeer populations in the six regionssampled are genetically differentiated withineach group and the two subspecies aredifferentiated from each other. A likelyexplanation for the genetic isolation of thepopulations investigated is that naturalbarriers (glaciers and wide fjords) exists inthe area. Furthermore we found that introducedNorwegian domestic reindeer hybridized with thenative Greenlandic caribou in two areasneighbouring Nuuk.     

A comparison of the growth of radio-tagged and dye-marked pike

Radio-tagged and dye-marked adult pike Esox lucius L. were recaptured in a reservoir 1 year after tagging. There was no significant difference in length or weight growth rate between the two groups of fish and no change in their condition factor.     

Malaria chemoprophylaxis in travellers to east Africa: a comparative prospective study of chloroquine plus proguanil with chloroquine plus sulfadoxine-pyrimethamine

As malaria caused by Plasmodium falciparum has become resistant to chloroquine alternative drug regimens need to be developed. The prophylactic efficacy against malaria and the side effects of chloroquine phosphate 500 mg weekly with proguanil hydrochloride 200 mg daily was compared with the efficacy of chloroquine 500 mg weekly with sulfadoxine 500 mg-pyrimethamine 25 mg weekly in a randomised study of Scandinavian travellers to Kenya and Tanzania during 1984-5. A total of 767 subjects (416 male and 351 female; 384 taking chloroquine phosphate with proguanil hydrochloride and 383 taking chloroquine with sulfadoxine-pyrimethamine) completed a diary on the breakthrough of malaria and the side effects of treatment while taking the drugs. They were also asked to make thick blood films when symptoms like those of malaria occurred, which were sent to and analysed in Denmark. Four subjects taking chloroquine with proguanil hydrochloride and three taking chloroquine with sulfadoxine-pyrimethamine developed falciparum malaria, which was verified microscopically. Side effects were reported by 36 subjects taking chloroquine phosphate with proguanil hydrochloride and 55 taking the other regimen (p=0·043). The side effects of both regimens were generally mild, but the combination of chloroquine phosphate with proguanil hydrochloride is recommended because it results in fewer side effects.As breakthroughs of malaria occurred at the earliest after seven weeks self treatment should not be recommended for travellers staying only a short time. Thick blood films are useful for diagnosis of suspected cases of malaria, can be prepared by non-specialists in Africa, and can be analysed successfully after long delays.     

Fermentation studies of the secretion of Serratia marcescens nuclease by Escherichia coli

The secretion of a Serratia marcescens nuclease was followed by fermentation with Escherichia coli. A plasmid, p403-SD2, carrying a 1.3-kilobase-pair insert with a 0.4-kilobase-pair region upstream of the nuclease gene caused a growth-phase-regulated expression of nuclease in E. coli in the same way as that seen in S. marcescens. Deletion of the regulatory gene generating plasmid p403-Rsa1 resulted in a constitutive expression of the nuclease. Anaerobiosis stimulated the expression from p403-SD2 in stationary growth phase by a factor of 10 compared with expression stimulated by cultivation in aerobic conditions; no such effect was found for plasmid p403-Rsa1. Different nutritional factors caused the expression level and the amount of extracellular nuclease to vary more when nuclease was expressed from plasmid p403-SD2 than when it was expressed from plasmid p403-Rsa1. A correlation between the regulatory gene and the extracellular secretion of nuclease is proposed.     

Osseointegration of preformed polymethylmethacrylate craniofacial prostheses coated with bone marrow-impregnated poly (DL-lactic-co-glycolic acid) foam.

Osseointegration of bone marrow-PLGA-coated, preformed polymethylmethacrylate cranioplasties offers the possibility of reducing: operative time, periimplant seroma and infection, metallic fixation, and periprosthetic resorption following surgical skull remodeling. These alloplastic materials are FDA-approved but previously have not been used together to promote cranioplasty incorporation. The objective of this study was to determine whether the use of PLGA foam coating improves host osseointegration of preformed, textured, polymethylmethacrylate prosthetic cranioplasties. A critical-sized cranial defect was created in two groups of 10 and one group of three rabbits. The defect was filled with either a textured, preformed polymethylmethacrylate disc or a textured, preformed polymethylmethacrylate disc coated with poly (DL-lactic-co-glycolic acid). Both implants were immersed in autologous bone marrow for 20 minutes before implantation. Half of each group of 10 were killed at 3 weeks, and the remainder at 6 weeks. A third group of three rabbits with excised periosteum was evaluated at 6 weeks. Histologic analysis of the discs determined relative amounts of cancellous bone formation adjacent to the prostheses. Woven trabecular bone was present at each host bone to implant perimeter interface at 3 weeks, with fine fibrous capsular formation around the implants. Thicker, lamellar trabeculae were present at 6 weeks with an increased fibrous layer surrounding both types of implants. Bone formed on the superficial and deep implant surfaces in a noncontiguous fashion. Two of five measures showed that total bone formation was significantly greater in the PLGA-coated implants. Polymethylmethacrylate discs coated with bone marrow-impregnated PLGA foam demonstrate increased bone formation at 3 and 6 weeks as compared with non-coated preformed polymethylmethacrylate discs. Only implants with preserved periosteum showed bone formation away from the host-implant interface (centrally) on the superficial surface at 6 weeks.     

Multiple Comparisons of Treatments with Stable Multivariate Tests in a Two‐Stage Adaptive Design,Including a Test for Non‐Inferiority

The application of stabilized multivariate tests is demonstrated in the analysis of a two‐stage adaptive clinical trial with three treatment arms. Due to the clinical problem, the multiple comparisons include tests of superiority as well as a test for non‐inferiority, where non‐inferiority is (because of missing absolute tolerance limits) expressed as linear contrast of the three treatments. Special emphasis is paid to the combination of the three sources of multiplicity – multiple endpoints, multiple treatments, and two stages of the adaptive design. Particularly, the adaptation after the first stage comprises a change of the a‐priori order of hypotheses.