Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression. RESULTS: Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54-7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29-5.40, p = 0.01). CONCLUSION: Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.

Short telomeres on human chromosome 17p.

Human chromosomes terminate in a series of T2AG3 repeats, which, together with associated proteins, are essential for chromosome stability. In somatic cells, these sequences are known to be gradually lost through successive cells divisions; however, information about changes on specific chromosomes is not available. Individual telomeres could mediate important biological effects as was shown in yeast, in which loss of a single telomere results in cell-cycle arrest and chromosome loss. We now demonstrate by quantitative fluorescence in situ hybridization (Q-FISH; ref. 7) that the number of T2AG3 repeats on specific chromosome arms is very similar in different tissues from the same donor and varies only to some extent between donors. In all sixteen individuals studied, telomeres on chromosome 17p were shorter than the median telomere length--a finding confirmed by analysis of terminal restriction fragments from sorted chromosomes. These observations provide evidence of chromosome-specific factors regulating the number of T2AG3 repeats in individual telomeres and raise the possibility that the relatively short telomeres on chromosome 17p contribute to the frequent loss of 17p alleles in human cancers.

Effects of Controlled Whole-body Vibration Training on Balance and Fall Outcomes Among Healthy Older Adults: A 6-Week Pilot Study.

Background: Falling is the second leading cause of injury-related death worldwide and is a leading cause of injury among older adults. Whole-body vibration has been used to improve balance and reduce fall risk in older adults. No study has assessed if vibration benefits can be retained over time. Objectives: The aims of this study were to examine if six-weeks of whole-body vibration could improve balance and fall outcomes, and to assess if benefits associated with the training program could be sustained two months following the final training session. Design and Setting: Repeated measures randomized controlled design. Participants: Twenty-four independent living older adults were recruited and were randomly assigned to the whole-body vibration or control group. Intervention: Participants performed three sessions of whole-body vibration training per week with a vibration frequency of 20 Hz or with only an audio recording of the vibration noise. An assessment of balance and fall outcomes was performed prior to, immediately following, and two-months after the completion of the training program. Main Outcome Measures: Composite balance scores from the Berg Balance Scale and treadmill fall rates were assessed pre-training, post-training, and two-months post-training. Results: Seventeen participants completed the study. No between groups differences were found (p<0.05) in the measures of balance or fall rates. Conclusions: Findings revealed that six weeks of whole-body vibration was not effective in improving balance scores or fall rates.

Effects of Controlled Whole-Body Vibration Training on Functional Performance Among Healthy Older Adults: A 6-Week Pilot Study.

Background: Falling is the second leading cause of injury-related death worldwide and is a leading cause of injury among older adults. Whole-body vibration has been used to improve fall risk factors in older adults. No study has assessed if vibration benefits can be retained over time. Objectives: The aims of this study were to examine if six-weeks of whole-body vibration could improve fall risk factors and to assess if benefits associated with the training program could be sustained two months following the final training session. Design and Setting: Repeated measures randomized controlled design. Participants: Twenty-four independent living older adults were recruited and were randomly assigned to the WBV or control group. Intervention: Participants performed three sessions of whole-body vibration training per week with a vibration frequency of 20Hz or with only an audio recording of the vibration noise. An assessment of fall risk factors was performed prior to, immediately following, and two-months after the completion of the training program. Main Outcome Measures: Fall risk factors including functional capacity, mobility, strength, and walking speed were assessed pre-training, post-training, and two-months post-training. Results: Seventeen participants completed the study. No improvements (p<0.05) between groups were found in the measures of physical performance. Conclusions: Findings revealed that six weeks of whole-body vibration is not effective in improving fall risk factors or producing benefits post-training.

Extension of cell life-span and telomere length in animals cloned from senescent somatic cells.

The potential of cloning depends in part on whether the procedure can reverse cellular aging and restore somatic cells to a phenotypically youthful state. Here, we report the birth of six healthy cloned calves derived from populations of senescent donor somatic cells. Nuclear transfer extended the replicative life-span of senescent cells (zero to four population doublings remaining) to greater than 90 population doublings. Early population doubling level complementary DNA-1 (EPC-1, an age-dependent gene) expression in cells from the cloned animals was 3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old) controls. Southern blot and flow cytometric analyses indicated that the telomeres were also extended beyond those of newborn (<2 weeks old) and age-matched control animals. The ability to regenerate animals and cells may have important implications for medicine and the study of mammalian aging.

Telomere instability in a human cancer cell line.

Telomere maintenance is essential in immortal cancer cells to compensate for DNA lost from the ends of chromosomes, to prevent chromosome fusion, and to facilitate chromosome segregation. However, the high rate of fusion of chromosomes near telomeres, termed telomere association, in many cancer cell lines has led to the proposal that some cancer cells may not efficiently perform telomere maintenance. Deficient telomere maintenance could play an important role in cancer because telomere associations and nondisjunction have been demonstrated to be mechanisms for genomic instability. To investigate this possibility, we have analyzed the telomeres of the human squamous cell carcinoma cell line SQ-9G, which has telomere associations in approximately 75% of the cells in the population. The absence of detectable telomeric repeat sequences at the sites of these telomere associations suggests that they result from telomere loss. The analysis of telomere length by quantitative in situ hybridization demonstrated that, compared to the human squamous cell carcinoma cell line SCC-61 which has few telomere associations, SQ-9G has more extensive heterogeneity in telomere length and more telomeres without detectable telomeric repeat sequences. The dynamics of the changes in telomere length also demonstrated a higher rate of fluctuation in telomere length, both on individual telomeres and coordinately on all telomeres. These results demonstrate that telomere maintenance can play a role in the genomic instability seen in cancer cells.

Multicolor fluorescence in situ hybridization with peptide nucleic acid probes for enumeration of specific chromosomes in human cells.

In previous studies, we showed that peptide nucleic acid (PNA) probes have significant advantages over conventional synthetic RNA or DNA probes in FISH procedures for detecting telomeric and trinucleotide repeat sequences. Here, we report that directly labeled PNA probes recognizing chromosome-specific repeat sequences are also powerful tools for detecting and enumerating specific chromosomes in interphase and metaphase cells. This is illustrated by multicolor FISH experiments with cells from normal individuals and patients with numerical sex chromosome aberrations.

Accumulation of short telomeres in human fibroblasts prior to replicative senescence.

The loss of telomere repeats has been causally linked to in vitro replicative senescence of human diploid fibroblasts (HDFs). In order to study the mechanism(s) by which telomere shortening signals cell senescence, we analyzed the telomere length at specific chromosome ends at cumulative population doublings in polyclonal and clonal HDFs by quantitative fluorescence in situ hybridization. The rate of telomere shortening at individual telomeres varied between 50 and 150 bp per population doubling and short telomeres with an estimated 1-2 kb of telomere repeats accumulated prior to senescence. The average telomere length in specific chromosome ends was remarkably similar between clones. However, some exceptions with individual telomeres measuring 0.5-1 kb were observed. In the fibroblast clones, the onset of replicative senescence was significantly correlated with the mean telomere fluorescence but, strikingly, not with chromosomes with the shortest telomere length. The accumulation of short telomeres in late passages of cultured HDFs is compatible with selection of cells on the basis of telomere length and limited recombination between telomeres prior to senescence.

Optimum fishing strategies for Isostichopusfuscus (Echinodermata: Holothuroidea) in the Gulf Of California, Mexico

The Isostichopus fuscus fishery in Mexico was heavily exploited until 1994, when it was closed due to overfishing. However, no information existed on the status of the populations. The fishery was evaluated through an age structured simulation model, and according to our analysis of the stock, the fishery can be feasible and sustainable as long as fishing mortality and age of first catch are optimized. In order to evaluate exploitation strategies, several scenarios were simulated considering different combinations of fishing intensities and ages of first catch. Input data for the model included population parameters, commercial catch and costs and benefits of the fishing operations. Yield production was strongly influenced by the fishing pressure and by the age of first capture. When the first one increased, significant decreases in yield and profits occurred. The best exploitation strategy was these parameters: fishing mortality level F = 0.15, age at first capture t(c) = 4 years, and yielding of approximately 430 tons. However, since the species reproduces for the first time at 5 years, extracting younger specimens would collapse the population. The critical value of fishing mortality was detected at Fc = 0.25. If exceeded, the population tends to exhaustion and the fishery is no longer profitable. In conclusion, I. fuscus fishery is highly vulnerable to overfishing and age of catch. It must be taken into account that the management policies should be considered as pilot and used on a regional basis. Continuous monitoring of the stock, control of the number of fishing licenses and extracting only specimens 5 yeasr-old and older (around 20 cm and >400 g), will allow the populations to recover from fishing activities