Exercise training in childhood-onset systemic lupus erythematosus: a controlled randomized trial

Introduction

Exercise training has emerged as a promising therapeutic strategy to counteract physical dysfunction in adult systemic lupus erythematosus. However, no longitudinal studies have evaluated the effects of an exercise training program in childhood-onset systemic lupus erythematosus (C-SLE) patients. The objective was to evaluate the safety and the efficacy of a supervised aerobic training program in improving the cardiorespiratory capacity in C-SLE patients.

Methods

Nineteen physically inactive C-SLE patients were randomly assigned into two groups: trained (TR, n = 10, supervised moderate-intensity aerobic exercise program) and non-trained (NT, n = 9). Gender-, body mass index (BMI)- and age-matched healthy children were recruited as controls (C, n = 10) for baseline (PRE) measurements only. C-SLE patients were assessed at PRE and after 12 weeks of training (POST). Main measurements included exercise tolerance and cardiorespiratory measurements in response to a maximal exercise (that is, peak VO₂, chronotropic reserve (CR), and the heart rate recovery (ΔHRR) (that is, the difference between HR at peak exercise and at both the first (ΔHRR1) and second (ΔHRR2) minutes of recovery after exercise).

Results

The C-SLE NT patients did not present changes in any of the cardiorespiratory parameters at POST (P > 0.05). In contrast, the exercise training program was effective in promoting significant increases in time-to-exhaustion (P = 0.01; ES = 1.07), peak speed (P = 0.01; ES = 1.08), peak VO₂ (P = 0.04; ES = 0.86), CR (P = 0.06; ES = 0.83), and in ΔHRR1 and ΔHRR2 (P = 0.003; ES = 1.29 and P = 0.0008; ES = 1.36, respectively) in the C-SLE TR when compared with the NT group. Moreover, cardiorespiratory parameters were comparable between C-SLE TR patients and C subjects after the exercise training intervention, as evidenced by the ANOVA analysis (P > 0.05, TR vs. C). SLEDAI-2K scores remained stable throughout the study.

Conclusion

A 3-month aerobic exercise training was safe and capable of ameliorating the cardiorespiratory capacity and the autonomic function in C-SLE patients.

Trial registration

NCT01515163.     

Automated Entire Thrombus Density Measurements for Robust and Comprehensive Thrombus Characterization in Patients with Acute Ischemic Stroke

Background and Purpose

In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements.

Materials and Method

In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described using medians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between the median of entire thrombus measurements and commonly applied manual measurements using 3 regions of interest were determined using linear regression.

Results

Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density.

Conclusions

Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, discrimination of low and high density thrombi is improved with the automated method.     

Towards a framework for the evolutionary genomics of Kinetoplastids: what kind of data and how much?

The current status of kinetoplastids phylogeny and evolution is discussed in view of the recent progresses on genomics. Some ideas on a potential framework for the evolutionary genomics of kinetoplastids are presented.     

The role of intravascular ultrasound imaging in vascular brachytherapy

Intracoronary brachytherapy has recently emerged as a new therapy to prevent restenosis. Initial experimental work was achieved in animal models and the results were assessed by histomorphometry. Initial clinical trials used angiography to guide dosimetry and to assess efficacy. Intravascular ultrasound (IVUS) permits tomographic examination of the vessel wall, elucidating the true morphology of the lumen and transmural components, which cannot be investigated on the lumenogram obtained by angiography. This paper reviews the use of IVUS in the clinical studies of brachytherapy conducted to date. IVUS allows clinicians to make a thorough assessment of the remodeling of the vessel and appears to have a major role to play in facilitating understanding of the underlying mechanisms of action in this emerging field. The authors propose that state-of-the-art IVUS techniques should be employed to further knowledge of the mechanisms of action of brachytherapy in atherosclerotic human coronary arteries.     

Improving model construction of profile HMMs for remote homology detection through structural alignment

Background  

Remote homology detection is a challenging problem in Bioinformatics. Arguably, profile Hidden Markov Models (pHMMs) are one of the most successful approaches in addressing this important problem. pHMM packages present a relatively small computational cost, and perform particularly well at recognizing remote homologies. This raises the question of whether structural alignments could impact the performance of pHMMs trained from proteins in the Twilight Zone, as structural alignments are often more accurate than sequence alignments at identifying motifs and functional residues. Next, we assess the impact of using structural alignments in pHMM performance.     

Infection with Strains of Citrus Tristeza Virus Does Not Exclude Superinfection by Other Strains of the Virus

Superinfection exclusion or homologous interference, a phenomenon in which a primary viral infection prevents a secondary infection with the same or closely related virus, has been observed commonly for viruses in various systems, including viruses of bacteria, plants, and animals. With plant viruses, homologous interference initially was used as a test of virus relatedness to define whether two virus isolates were “strains” of the same virus or represented different viruses, and subsequently purposeful infection with a mild isolate was implemented as a protective measure against isolates of the virus causing severe disease. In this study we examined superinfection exclusion of Citrus tristeza virus (CTV), a positive-sense RNA closterovirus. Thirteen naturally occurring isolates of CTV representing five different virus strains and a set of isolates originated from virus constructs engineered based on an infectious cDNA clone of T36 isolate of CTV, including hybrids containing sequences from different isolates, were examined for their ability to prevent superinfection by another isolate of the virus. We show that superinfection exclusion occurred only between isolates of the same strain and not between isolates of different strains. When isolates of the same strain were used for sequential plant inoculation, the primary infection provided complete exclusion of the challenge isolate, whereas isolates from heterologous strains appeared to have no effect on replication, movement or systemic infection by the challenge virus. Surprisingly, substitution of extended cognate sequences from isolates of the T68 or T30 strains into T36 did not confer the ability of resulting hybrid viruses to exclude superinfection by those donor strains. Overall, these results do not appear to be explained by mechanisms proposed previously for other viruses. Moreover, these observations bring an understanding of some previously unexplained fundamental features of CTV biology and, most importantly, build a foundation for the strategy of selecting mild isolates that would efficiently exclude severe virus isolates as a practical means to control CTV diseases.Superinfection exclusion or homologous interference is a phenomenon in which a preexisting viral infection prevents a secondary infection with the same or a closely related virus, whereas infection by unrelated viruses can be unaffected. The phenomenon was first observed by McKinney (57, 58) between two genotypes of Tobacco mosaic virus (TMV) and later with bacteriophages (21, 94). Since that time, the phenomenon has been observed often for viruses of animals (1, 13, 18, 34, 43, 47, 50, 85, 86-88, 102, 103) and plants (11, 30, 31, 32, 39, 40, 49, 77, 99, 100). In plant virology, homologous interference initially was used as a test of virus relatedness to define whether two virus isolates were “strains” of the same virus or represented different viruses (58, 77). Subsequently, it was developed into a management tool to reduce crop losses by purposely infecting plants with mild isolates of a virus to reduce infection and losses due to more severe isolates, which is referred to as “cross-protection” (reviewed in references 32 and 40).Homologous superinfection exclusion of animal viruses has been related to several mechanisms acting at various stages of the viral life cycle, including prevention of the incoming virus entry into cells (50, 86, 87), or inhibition of translation or interference with replication (1, 47, 50, 83). Several mechanisms have been postulated for homologous interference of plant viruses, including prevention of the disassembly of the challenge virus as it enters the cell resulting from the expression of the coat protein of the protector virus (67, 84; reviewed in reference 10) and induction of RNA silencing by the protector virus that leads to sequence-specific degradation of the challenge virus RNA (24, 69, 70). However, common mechanisms of superinfection exclusion, expected to be associated with the viruses of plants and animals, have not been elucidated.Citrus tristeza virus (CTV) is the largest and most complex member of the Closteroviridae family, which contains viruses with mono-, bi-, and tripartite genomes transmitted by a range of insect vectors, including aphids, whiteflies, and mealybugs (3, 6, 19, 20, 46). CTV has long flexuous virions (2,000 nm by 10 to 12 nm) encapsidated by two coat proteins and a single-stranded RNA genome of ∼19.3 kb. The major coat protein (CP) covers ca. 97% of the genomic RNA, and the minor coat protein (CPm) completes encapsidation of the genome at its 5′ end (25, 81). The RNA genome of CTV encodes 12 open reading frames (ORFs) (44, 64) (Fig. ​(Fig.1).1). ORFs 1a and 1b are expressed from the genomic RNA and encode polyproteins required for virus replication. ORF 1a encodes a 349-kDa polyprotein containing two papainlike protease domains plus methyltransferaselike and helicaselike domains. Translation of the polyprotein is thought to occasionally continue through the polymerase-like domain (ORF 1b) by a +1 frameshift. Ten 3′-end ORFs are expressed by 3′-coterminal subgenomic RNAs (sgRNAs) (37, 45) and encode the following proteins: major (CP) and minor (CPm) coat proteins, p65 (HSP70 homolog), and p61 that are involved in assembly of virions (79); a hydrophobic p6 protein with a proposed role in virus movement (20, 89); p20 and p23, which along with CP are suppressors of RNA silencing (54); and p33, p13, and p18, whose functions remain unknown. Remarkably, citrus trees can be infected with mutants with three genes deleted: p33, p18, and p13 (89).Open in a separate windowFIG. 1.(A) Schematic diagram of the genome organization of wild-type CTV (CTV9R) and its derivative CTV-BC5/GFP encoding GFP. The open boxes represent ORFs and their translation products. PRO, papainlike protease domain; MT, methyltransferase; HEL, helicase; RdRp, an RNA-dependent RNA polymerase; HSP70h, HSP70 homolog; CPm, minor coat protein; CP, major coat protein; GFP, green fluorescent protein. Bent arrows indicate positions of BYV (B_CP) or CTV CP (C_CP) sgRNA controller elements. Inserted elements are shown in gray. (B) Scheme of the “superinfection exclusion assay.” Young Madam Vinous sweet orange trees were initially inoculated with one of 13 tested CTV isolates. When primary infections were established, the trees were subsequently challenged with CTV-BC5/GFP. All inoculations were done by grafting of the infected tissue into the stem of a tree. The positions of primary (Pri) and challenge (Chl) graft inoculations are shown. The ability of the challenge virus to superinfect trees was determined by visual observation of GFP fluorescence in phloem-associated cells on the internal surface of bark from a young flash starting at about 2 months upon challenge inoculation. Scale bar, 0.4 mm.The host range of CTV is limited to citrus in which the virus infects only phloem-associated cells. CTV consists of numerous isolates that have distinctive biological and genetic characteristics (38, 48, 56, 72, 74, 75, 95). Recently, a classification strategy for CTV isolates was proposed based on sequence similarity. Analysis of nearly 400 isolates in an international collection revealed five major CTV genotype groups with some isolates undefined (38). For the purposes of the present study, strains are defined as phylogenetically distinct lineages of CTV based upon analysis of nucleotide sequences of the 1a ORF (38). This region of the genome shows high genetic diversity between CTV variants, with levels of sequence identity ranging between 72.3 to 90.3% (38, 48, 52, 74, 75; M. Hilf, unpublished data). Using this definition, T3, T30, T36, VT, and T68 are designated as strains. Individual virus samples are designated as isolates of one of these strains. The ORF 1a nucleotide sequences of isolates of the T36 and T68 strains are equally dissimilar to isolates of the T3, T30, and VT strains, with identities of 72.9, 73, and 72.4% and 77.6, 77.9, and 76.8%, respectively. Identities of ORF 1a range from 89.4 to 90.3% between isolates of the T3, T30, and VT strains. Sequences of ORF1a of isolates belonging to the T36 strain and those from the T68 strain show 72.3% identity. This compares to a range of 89 to 94.8% identity found in the more conserved 3′-half regions of the genomes of isolates from different CTV strains. Each strain is named after a “type isolate” and is composed of isolates with minor sequence divergence (generally less than 5% throughout genome) from the type member. However, isolates of a strain may have significant variations in symptoms and symptoms severity. Remarkably, field trees harbor complex populations of CTV, which are often composed of mixtures of different strains and recombinants between these strains (36, 48, 52, 68, 75, 96, 101). The genetic basis of such frequent coexistence of different strains within the same tree is unknown.CTV causes economically important diseases of citrus worldwide. One of the most effective management tools has been cross-protection when effective protecting isolates could be found. Preinfection with mild isolates allows commercial production of sweet oranges and limes in Brazil (16) and Peru (9) and grapefruit in South Africa (92). However, identification of protecting isolates has been empirical, difficult, and rare. Cross-protection usually has worked only in certain varieties, and the lack of effective protecting isolates has prevented its use in many varieties and citrus growing areas (15, 41, 61, 73). In general, there has been no understanding why some mild isolates were effective and others failed to protect. Because CTV diseases prevail in citrus growing areas worldwide, elucidation of the mechanisms of exclusion of one CTV variant by another one is an important goal.In the present study we examined relationships between different genotypes of CTV in terms of their ability to prevent superinfection by another isolate of the virus. We show that superinfection exclusion occurred only between minor genetic variants of the same strain (sequence group) and not between isolates of different strains. When isolates of the same strain were used for sequential plant inoculation, the primary infection provided full exclusion of the challenge isolate. In all combinations of virus isolates belonging to different strains, the primary infection of plants with one strain had no noticeable effect on the establishment of the secondary infection. The results obtained here help elucidate some previously unexplained fundamental features of CTV biology and pose the possibility of an existence of a novel mechanism for superinfection exclusion between virus variants.