Association of Baseline Frailty with Patient-Reported Outcomes in Systemic Lupus Erythematosus at 1 Year.

The relationship of baseline frailty with subsequent patient-reported outcomes in systemic lupus erythematosus (SLE) remains unclear. We assessed these associations in a pilot prospective cohort study. Frailty based on the FRAIL scale and the Fried phenotype and patient-reported outcomes, namely Patient Reported Outcomes Measurement Information System computerized adaptive tests and Valued Life Activities disability, were measured at baseline and 1 year among women aged 18-70 years with SLE enrolled at a single center. Differences in Patient Reported Outcomes Measurement Information System computerized adaptive tests between frail and non-frail participants were evaluated using Wilcoxon rank sum tests, and the association of baseline frailty with self-report disability at 1 year was estimated using linear regression. Of 51 participants, 24% (FRAIL scale) and 16% (Fried phenotype) met criteria for frailty at baseline despite median age of 55.0 and 56.0 years, respectively. Women with (versus without) baseline frailty using either measure had worse 1-year Patient Reported Outcomes Measurement Information System computerized adaptive test scores across multiple domains and greater self-report disability. Baseline frailty was significantly associated with self-report disability at 1 year (FRAIL scale: parameter estimate 0.55, 95% confidence interval (CI) 0.21-0.89, p<0.01; Fried phenotype: parameter estimate 0.61, 95% CI 0.22-1.00, p<0.01), including only slight attenuation after adjustment for SLE cumulative organ damage (FRAIL scale: parameter estimate 0.45, 95% CI 0.09-0.81, p=0.02; Fried phenotype: parameter estimate 0.49, 95% CI 0.09-0.90, p=0.02). These preliminary findings support frailty as an independent risk factor for clinically relevant patient-reported outcomes, including disability onset, among women with SLE.

Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia.

BACKGROUND: Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. METHODS: In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7 ± 3.5 years at diagnosis, median 2.5 years after therapy; males: 28). INCLUSION CRITERIA: ≥6 years of age, ≥3 months after last administration of Vincristine, and cumulative dose of Vincristine 12 mg/m2. We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped-mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment of small- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large-fiber neuropathy. RESULTS: Fifteen survivors (33%) had abnormal rPed-mTNS values (≥4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p < 0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. CONCLUSION: QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival.

Inverse PPARß/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARß/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARß/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor ß (TGFß)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARß/δ target in MDA-MB-231 cells, previously implicated in TGFß-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFß and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARß/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARß/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARß/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARß/δ agonists is feasible.

IL2 and TNFA gene polymorphisms and the risk of graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

This study aimed to analyse the association of gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. We studied 122 donor/recipient pairs who received HLA-identical transplants from siblings at the Universidade Estadual de Campinas, Brazil, between June 1996 and June 2006. Donor/recipient alleles for TNFA-238 and IL2-330/+166 single-nucleotide polymorphisms (SNP) were analysed by PCR-SSP. No association was observed between the risk of acute graft-versus-host disease (GVHD) and these SNP. However, our findings suggest that the polymorphism of promoter gene TNFA-238GA is associated with the occurrence and severity of chronic GVHD. The probability of chronic GVHD in patients with GA genotype at position -238 of TNFA gene is 91.7% in contrast to 59.4% in patients with GG genotype (P = 0.038). In patients with donor GA genotype the probability of chronic GVHD is 90.8%, and 57.9% in patients with donor GG genotype (P = 0.038). The probability of extensive chronic GVHD in patients with TNFA-238GA is 91.7% compared with 46.3% in patients with TNFA-238GG (P = 0.0046). In patients with donor GA genotype at position -238 of the TNFA gene, it is 81.7%, compared with 44.5% in patients with donor GG genotype (P = 0.016). However, further studies with more patients are required to identify cytokine gene polymorphisms and their association with transplant-related complication in Brazil, particularly due to ethnic background, the relatively low power of detection of genetic markers of this study, and the complexity of the MHC region.

Effect of panel-reactive antibody in predicting crossmatch selection of cadaveric kidney recipients.

AIM: The influence of panel-reactive antibody level (%PRA) on crossmatch results was evaluated among 866 patients on the waiting list for cadaveric renal allografting from January 2001 to August 2005. We evaluated the results for 124 potential donors for a kidney, including 2008 crossmatches. Four hundred eighteen patients were tested against only 1 donor. METHODS: Serum samples were screened for anti-HLA antibodies using immunoglobulin (Ig)G enzyme-linked immunosorbent assay (ELISA) PRA kit and the %PRA of the most reactive sample (peak) was used for patient stratification, according to sensitization level. Crossmatches were performed on fresh donor T lymphocytes from peripheral lymph nodes, using classical and anti-human-globulin enhanced complement-dependent cytotoxicity (CDC-T) methods. The tests were performed using peak and current patient sera before and after dithiothreitol treatment. The crossmatch was assumed to be negative when no reactivity was observed in all tests. RESULTS: The incidences of positive crossmatch were as follows: 72.3%, 14.6%, and 7.2%, among patients with PRA >50%, PRA

Gender-specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts.

We utilized proteomic techniques in a primate model (Macaca fascicularis) of aging to determine potential mechanisms to explain gender differences in protection of the aging heart. The majority of prior work in this field utilized rodent models, and importantly no prior study utilized a proteomic approach in the aging heart. We studied changes in proteins in seven monkeys in each group (young and old males and females (YMs, OMs, YFs, and OFs, respectively)), and used two-dimensional gel electrophoresis in combination with mass spectrometry in five monkeys in each group. We found decreases (P < 0.05) in the expression of key enzymes in glycolysis (e.g. pyruvate kinase, alpha-enolase, triosephosphate isomerase), glucose oxidation (e.g. pyruvate dehydrogenase E1 beta-subunit), and the tricarboxylic acid (TCA) cycle (2-oxoglutarate dehydrogenase) in left ventricular (LV) samples from OM monkeys; these changes in glycolytic, glucose oxidation, and TCA enzymes were not observed either in YMs, YFs or OFs. We found additional gender differences in the reduced expression and function of proteins that are responsible for electron transport and oxidative phosphorylation in mitochondria only in hearts from OM monkeys, with corresponding decreased oxidation rates with NADH and ascorbate-N,N,N',N' ''-tetramethyl-p-phenylenediamine substrates. The changes in glycolytic and mitochondrial metabolic pathways in OM monkey hearts are similar to changes observed in hearts affected by diabetes or LV dysfunction, and could be involved in the mechanism for the cardiomyopathy of aging. The sparing of these changes in OF hearts could be involved in the mechanism mediating delayed cardiovascular risk in OFs.

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation.

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3%) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6%). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7%, with a median of 0.5%. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5% than in those with RR < or =4.5%. The Cox Proportional Hazards model was used to examine the effect of MLC levels on incidence of chronic GVHD, while adjusting for the potential confounding effect of others suspected or observed risk factors. The relative risk of chronic GVHD was 2.5 for patients with positive MLC (RR >4.5%), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5% associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication.

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3 percent) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6 percent). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7 percent, with a median of 0.5 percent. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5 percent than in those with RR <=4.5 percent. The Cox Proportional Hazards model was used to examine the effect of MLC levels on incidence of chronic GVHD, while adjusting for the potential confounding effect of others suspected or observed risk factors. The relative risk of chronic GVHD was 2.5 for patients with positive MLC (RR >4.5 percent), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5 percent associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication

Effects of body mechanics training on performance of repetitive lifting.

OBJECTIVE: To measure the efficacy of body mechanics instruction (BMI) in patients with low back pain. METHOD: The effect of BMI was measured in four participants with back injuries using a standardized lifting protocol. Static strength, weight lifted, number of lifts completed, and motion analysis data to describe the body mechanics were measured before and after work hardening to evaluate treatment effects. The participants' performances were compared with 52 controls from an earlier study. RESULTS: Starting postures, characterized by degrees of hip and knee flexion, varied by participant but favored a squat lift in three participants when compared with the controls. Dynamic motion synchrony of the hip and knee joints was similar to controls in three of the four participants. Posttest data revealed significant changes in static strength, dynamic endurance, and lifting speed. CONCLUSION: Intensive instruction in body mechanics provided during the work-hardening treatment produced major changes in lifting styles, in terms of both starting postures and dynamic aspects of repetitive lifting. The computerized measurement procedures used in this study permitted more careful and detailed analyses of body mechanics, particularly dynamic aspects, than is possible with observational methods. This study demonstrated some of the inherent intricacies in isodynamic lifting and suggests additional areas of performance that may be important to address in BMI.

Distribution of HLA-DRB1 alleles in a mixed population with insulin-dependent diabetes mellitus from the southeast of Brazil.

HLA class II genes are strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). The present study reports the HLA-DRB1 genotyping of 41 IDDM patients and 99 healthy subjects from the Southeast of Brazil (Campinas region). Both groups consisted of an ethnic mixture of Caucasian, African Negro and Amerindian origin. HLA-DRB1*03 and *04 alleles were found at significantly higher frequencies among IDDM patients compared to the controls (DRB1*03: 48.8% vs 18.2%, P < 0.005, RR = 4.27; DRB1*04: 43.9% vs 15.1%, P < 0.008, RR = 4.37) and were associated with a susceptibility to the disease. DRB1*03/*04 heterozygosity conferred a strong IDDM risk (RR = 5.44). In contrast, the HLA-DRB1*11 allele frequency was lower among IDDM patients (7.3% vs 26.3% in controls), but the difference was not significant. These data agree with those described for other populations and allow genetic characterization of IDDM in Brazil.

Distribution of HLA-DRB1 alleles in a mixed population with insulin-dependent diabetes mellitus from the Southeast of Brazil

HLA class II genes are strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). The present study reports the HLA-DRB1 genotyping of 41 IDDM patients and 99 healthy subjects from the Southeast of Brazil (Campinas region). Both groups consisted of an ethnic mixture of Caucasian, African Negro and Amerindian origin. HLA-DRB1*03 and *04 alleles were found at significantly higher frequencies among IDDM patients compared to the controls (DRB1*03: 48.8 percent vs 18.2 percent, P<0.005, RR= 4.27); DRB1*04:43.9 percent vs 15.1 percent, P<0.008, RR=4.37) and were associated with a susceptibility to the disease. DRB1*03/*04 heterozygosity conferred a strong IDDM risk (RR=5.44). In contrast, the HLA-DRB1*11 allele frequency was lower among IDDM patients (7.3 percent vs 26.3 percent in controls), but the difference was not significant. These data agree with those described for other populations and allow genetic characterization of IDDM in Brazil.

Micronucleus monitoring to assess human occupational exposure to organochlorides.

Health surveillance for hazardous situations due to chemical exposure, in particular those which are carcinogenic, requires sensitive monitoring tests. Although experimental studies have shown the genotoxic and carcinogenic effect of several organochlorides, the lack of epidemiologic studies prevents their classification as carcinogenic to human beings. In this context, genotoxicity tests of short duration in human cells gain importance. The relation between the clastogenic effects (chromosome breaks) and cancer induction is already known to the scientific literature. The micronucleus test has been proposed as a good indicator of clastogenesis. In the present study, we evaluated, by means of the micronucleus test, 41 workers of a chemical industry in the state of São Paulo, southeast region of Brazil, who had been exposed to a mixture of chlorinated solvents (carbon tetrachloride, perchloroethylene, and hexachlorobenzene) and 28 workers who had not been exposed. Peripheral lymphocytes stimulated by phytohemagglutinin and with cytokinesis blocked by cytochalasin B were used. The results showed that the exposed workers presented a statistically significant higher frequency of micronuclei than the group which had not been exposed.

Diagnostic value and incremental contribution of bicycle exercise, first-pass radionuclide angiography, and 99mTc-labeled sestamibi single-photon emission computed tomography in the identification of coronary artery disease in patients without infarction.

BACKGROUND: The diagnostic value and incremental contribution of different noninvasive tests to the identification of coronary artery disease in 128 patients from a general population with intermediate pretest likelihood (48.0%) were determined by ordered logistic regression analysis and receiver-operating characteristic (ROC) curves. METHODS AND RESULTS: Patients referred for suspicion of coronary heart disease were submitted to bicycle exercise testing under clinical and electrocardiographic control. AT peak exercise, first-pass radionuclide angiography was performed after injection of 99mTc-labeled sestamibi, followed by single-photon emission computed tomographic (SPECT) acquisition. A comparative rest study was obtained within 1 week, and qualitative and quantitative analysis was applied to assess the presence and extent of disease. With coronary angiography and 50% stenosis used as a standard, the discriminative accuracy of each test was calculated. The accuracies to diagnose coronary heart disease were 71.3% +/- 4.7% for the bicycle test, 66.7% +/- 5.3% for radionuclide angiography, and 81.6% +/- 3.9% for the SPECT data. By ROC curves, the optimal criteria for positivity were determined for the visual and quantitative analysis for both presence and extent of coronary artery disease. Results of visual and quantitative SPECT were compared in terms of area under the ROC curves. The diagnostic performances showed no significant difference, ranging from 74.3% to 81.6%. The first-pass radionuclide angiographic and SPECT data were added progressively to the stress testing to evaluate their incremental diagnostic contribution. Only the addition of SPECT results significantly increased the accuracy to 85.6% +/- 3.3% (p < 0.0001). CONCLUSION: Exercise electrocardiography and first-pass radionuclide angiography showed comparable accuracy to detect coronary artery disease. However, the combination of exercise testing and visual SPECT analytic data sufficed to ensure diagnostic accuracy, without significant benefit from the addition of other tests or the application of quantification.

Functional capacity assessment: Influence of behavioral and environmental factors.

The environment surrounding the functional capacity evaluation (FCA) is complex and determined by both external factors as well as those specific to the testing situation. In this paper we (1) briefly review existing models of pain, (2) highlight how current FCAs of pain patients adhere in general to behavioral conceptualizations of chronic pain, (3) review some inadequacies of current conceptualizations of FCA when it applies to chronic pain, (4) review the many internal and external environmental factors that can significantly influence FCAs, and (5) consider some psychosocial factors that play an important role in patients' performances. We conclude that not only should evaluators more carefully consider the central influences of psychosocial factors when interpreting the results of FCAs, but that an alternate conceptual model that emphasizes both environmental and psychological factors is also needed to more adequately describe the physical performances obtained during FCAs.

Body motion patterns during a novel repetitive wheel-rotation task. A comparative study of healthy subjects and patients with low back pain.

STUDY DESIGN: This study evaluated performance differences between patients with chronic low back pain and a control group during their performance of a novel functional capacity task. OBJECTIVE: To 1) evaluated strength and endurance differences between patients and control subjects, 2) test for movement pattern differences between these groups, and 3) evaluate how these patterns changed with repetitive performance of the wheel-turning task. SUMMARY OF BACKGROUND DATA: Despite increased emphasis on quantifying functional capacities, few well-controlled studies comparing the performances of patients with low back pain with those of control subjects have appeared in the literature, particularly for movement patterns. METHODS: Forty patients with low back pain and 40 control subjects performed a sustained isodynamic wheel turning task. This task was selected because it simultaneously combined several common pain-related movements. A set of kinematic measures to characterize the basic movement patterns during this task were developed. RESULTS: Control subjects produced significantly higher levels of static torque and completed significantly more wheel-turning repetitions. Patients with low back pain exhibited significantly less upper torso and pelvic motion, upper torso rotation, and lateral trunk flexion than those in the control group. CONCLUSION: The dissimilar movement strategies found between the patient and control groups suggests that factors beyond more global physical explanations (e.g., deconditioning) may be important in accounting for the large discrepancy between these groups regarding the amount of work performed. These findings, along with the basic kinematic patterns developed in this study, may have important implications for determining the efficacy of instruction in body mechanics and treatment outcome for patients with chronic low back pain.

Measuring treatment effects on repetitive lifting for patients with chronic low back pain: speed, style, and coordination.

The purpose of this study was to determine changes in the amount of work performed and lifting speed, style, and coordination during a repetitive dynamic-lifting task for patients with chronic low back pain (CLBP) after an intensive 3 1/2-week pain rehabilitation program. Subjects included 57 CLBP patients and an age- and gender-matched control group (n = 57). Patients' work indices increased by 71%, but remained significantly less than those observed for controls. Similarly, their lifting speed also increased significantly after treatment, but remained slower than the lifting speed of controls. Patients' posttreatment coordination indices, however, were not significantly different from those of controls. This finding suggests that treatment effectively normalized the dynamic lifting motion used by the patients. These findings, along with the basic kinematic patterns developed in this study, have important implications for determining improvements in functional capacity in the treatment of patients with CLBP.