Racial disparities in stroke incidence in the Women's Health Initiative: Exploring biological, behavioral, psychosocial, and social risk factors.

Background: - Disparities in incident stroke risk among women by race and ethnicity persist. Few studies report the distribution and association of stroke risk factors by age group among a diverse sample of women. Methods: - Data from the Women's Health Initiative (WHI) Observational Study collected between 1993 and 2010 were used to calculate cumulative stroke incidence and incidence rates among non-Hispanic African American (NHAA), non-Hispanic white (NHW), and Hispanic white or African American (HWAA) women by age group in participants aged ≥50 years at baseline (N = 77,247). Hazard ratios (HRs) and 95% CIs for biological, behavioral, psychosocial, and socioeconomic factors overall and by race or ethnicity were estimated using sequential Cox proportional hazard regression models. Results: - Average follow-up time was 11.52 (SD, 3.48) years. The incident stroke rate was higher among NHAA (306 per 100,000 person-years) compared to NHW (279/100,000py) and HWAA women (147/100,000py) overall and in each age group. The disparity was largest at ages >75 years. The association between stroke risk factors (e.g., smoking, BMI, physical activity) and incident stroke varied across race and ethnicity groups. Higher social support was significantly associated with decreased stroke risk overall (HR:0.84, 95% CI, 0.76, 0.93); the degree of protection varied across race and ethnicity groups. Socioeconomic factors did not contribute additional stroke risk beyond risk conferred by traditional and psychosocial factors. Conclusions: - The distribution and association of stroke risk factors differed between NHAA and NHW women. There is a clear need for stroke prevention strategies that address factors driving racial disparities in stroke risk.

Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial.

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 ±â€…5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost -10.8 ±â€…0.9 kg (-11.3% ±â€…5.4%) over 18 weeks compared with +0.5 ±â€…0.9 kg (+0.03% ±â€…3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F = 4.17, p ≤ .05) and associated with the degree of weight loss (R2 = 0.12, p ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions.

Low-intensity pulsed ultrasound promotes proliferation and migration of HaCaT keratinocytes through the PI3K/AKT and JNK pathways.

Although the effects of low-intensity pulsed ultrasound (LIPUS) on diverse cell types have been fully studied, the functional role of LIPUS in keratinocytes remains poorly understood. This study aimed to investigate the effects of LIPUS on proliferation and migration of HaCaT cells as well as the regulatory mechanisms associated with signaling pathways. Human HaCaT cells were exposed or not to LIPUS, and cell proliferation and migration were measured by BrdU incorporation assay and Transwell assay, respectively. Expression of proteins associated with proliferation and migration was evaluated by western blot analysis. Expression of key kinases in the PI3K/AKT and JNK pathways was also evaluated by western blot analysis. Effects of LIPUS on the PI3K/AKT and JNK pathways, and whether LIPUS affected HaCaT cells via these two pathways were finally explored. When the parameter of LIPUS (number of cycles) was set at 300, cell viability was the highest after LIPUS stimulation. We then found that the percentage of BrdU positive cells was enhanced by LIPUS, along with up-regulation of cyclinD1, CDK6, CDK4, and VEGF. LIPUS promoted migration, as well as up-regulation of MMP-2 and MMP-9. Phosphorylation levels of key kinases in the PI3K/AKT and JNK pathways were increased by LIPUS. Inhibition of either PI3K/AKT pathway or JNK pathway attenuated effects of LIPUS on HaCaT cells, and co-inhibition of these two pathways showed augmented effects. LIPUS promoted proliferation and migration of HaCaT cells through activating the PI3K/AKT and JNK pathways.

Self-reported mobility as a preoperative risk assessment tool in older surgical patients compared to the American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP®) developed a surgical risk calculator using data from 1.4 million patients and including 1557 unique Current Procedural Terminology (CPT) codes. Although this calculator demonstrated excellent performance in predicting postoperative mortality, morbidity, and six surgical complications, it was not developed specifically for use in older surgical patients who have worse surgical outcomes and additional unique risk factors compared to younger adults. We aimed to test the ability of a simple self-reported mobility tool to predict postoperative outcomes in the older surgical population compared to the NSQIP. METHODS: We used data from a prospective cohort study that enrolled 197 older surgical patients (≥ 69 years) undergoing various elective surgeries and assessed 30-day surgical outcomes. Statistical models included data from the Mobility Assessment Tool-short form (MAT-sf) alone, covariates alone, and MAT-sf data and covariates. We used leave-one-out (LOO) cross-validation of the models within our cohort and compared their performance for predicting postoperative outcomes against the NSQIP calculator based on receiver operating characteristic area under the curve (ROC AUC). RESULTS: Patients with poor self-reported mobility experienced higher rates of postoperative complications and nursing home placement. There was no difference in performance between any of our models and the NSQIP calculator (p > 0.1), with AUC between 0.604 and 0.697 for predicting postoperative complications and 0.653 and 0.760 for predicting nursing home placement. All models also predicted a length of stay (LOS) similar to the actual LOS. CONCLUSION: Mobility assessment alone using MAT-sf can predict postoperative complications, nursing home placement, and LOS for older surgical patients, with accuracy comparable to that of the NSQIP calculator. The simplicity of this noninvasive risk assessment tool makes it an attractive alternative to the NSQIP calculator that requires 20 patient predictors and the planned procedure, or CPT code to predict the chance that patients will have 15 different adverse outcomes following surgery.

Low-intensity pulsed ultrasound promotes proliferation and migration of HaCaT keratinocytes through the PI3K/AKT and JNK pathways

Although the effects of low-intensity pulsed ultrasound (LIPUS) on diverse cell types have been fully studied, the functional role of LIPUS in keratinocytes remains poorly understood. This study aimed to investigate the effects of LIPUS on proliferation and migration of HaCaT cells as well as the regulatory mechanisms associated with signaling pathways. Human HaCaT cells were exposed or not to LIPUS, and cell proliferation and migration were measured by BrdU incorporation assay and Transwell assay, respectively. Expression of proteins associated with proliferation and migration was evaluated by western blot analysis. Expression of key kinases in the PI3K/AKT and JNK pathways was also evaluated by western blot analysis. Effects of LIPUS on the PI3K/AKT and JNK pathways, and whether LIPUS affected HaCaT cells via these two pathways were finally explored. When the parameter of LIPUS (number of cycles) was set at 300, cell viability was the highest after LIPUS stimulation. We then found that the percentage of BrdU positive cells was enhanced by LIPUS, along with up-regulation of cyclinD1, CDK6, CDK4, and VEGF. LIPUS promoted migration, as well as up-regulation of MMP-2 and MMP-9. Phosphorylation levels of key kinases in the PI3K/AKT and JNK pathways were increased by LIPUS. Inhibition of either PI3K/AKT pathway or JNK pathway attenuated effects of LIPUS on HaCaT cells, and co-inhibition of these two pathways showed augmented effects. LIPUS promoted proliferation and migration of HaCaT cells through activating the PI3K/AKT and JNK pathways.

Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults.

BACKGROUND: Low levels of the soluble receptor for advanced glycation endproducts (sRAGE) have been implicated in a number of chronic diseases. Previous studies indicate that sRAGE levels are ~30% lower in Blacks compared to Whites. However, the reasons for these differences are unclear. PURPOSE: We aimed to identify predictors of circulating sRAGE biomarkers among Black and White adults at high cardiac risk. METHODS: Serum levels of total sRAGE, endogenous secretory RAGE (esRAGE), carboxymethyl-lysine (CML, a major RAGE ligand), and their ratios were measured in 99 Blacks and 454 Whites. RESULTS: Blacks had a more adverse cardiovascular risk profile, as well as lower median levels of total sRAGE (972 vs. 1564pg/ml) and esRAGE (474 vs. 710pg/ml) compared to Whites (p<0.0001). In addition, the proportion of esRAGE was higher in Blacks (47% vs. 44%, p=0.02), as were the CML/total sRAGE (0.89 vs. 0.56ng/pg) and CML/esRAGE (1.72 vs. 1.20ng/pg) ratios (p<0.0001). Racial differences persisted after adjustment for key covariates including age, gender, tobacco use, comorbidities, BMI, blood pressure, glucose, insulin, triglycerides, C-reactive protein, and renal function (p<0.05). Race alone accounted for nearly half of the variability in total sRAGE levels (10.6%; model explained 23.9%). In stratified analyses, gender and heart rate were independently associated with total sRAGE and esRAGE in Whites, while CML and C-reactive protein were associated with total sRAGE in Blacks. CONCLUSIONS: We identified several independent predictors of sRAGE biomarkers. Notably, Black race was associated with an adverse AGE/RAGE profile, including lower sRAGE and higher CML/sRAGE ratios.

Self-reported Mobility in Older Patients Predicts Early Postoperative Outcomes after Elective Noncardiac Surgery.

BACKGROUND: Specific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery. METHODS: Patients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool-short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP). RESULTS: In the sample of this study (mean age, 75 ± 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge. CONCLUSIONS: Preoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events.

Physical Functioning among Women 80 Years of Age and Older With and Without a Cancer History.

BACKGROUND: Females 80 years and older comprise 22% of the total U.S. survivor population, yet the impact of cancer on the physical well-being of women is this age group has not been well characterized. METHODS: We compared women, 80 years of age and older in the Women's Health Initiative extension 2, who did (n = 2,270) and did not (n = 20,272) have an adjudicated history of cancer during Women's Health Initiative enrollment; analyses focused on women >2-years postcancer diagnosis. The physical functioning subscale of the RAND-36 was the primary outcome. Demographic, health-status, and psychosocial covariates were drawn from Women's Health Initiative assessments. Analysis of covariance was used to examine the effect of cancer history on physical function, with and without adjustment for covariates. RESULTS: In adjusted models, women with a history of cancer reported significantly lower mean physical functioning (56.6, standard error [SE] 0.4) than those without a cancer history (58.0, SE 0.1), p = .002. In these models, younger current age, lower body mass index, increased physical activity, higher self-rated health, increased reported happiness, and the absence of noncancer comorbid conditions were all associated with higher physical functioning in both women with and without a history of cancer. CONCLUSIONS: Women older than 80 years of age with a cancer history have only a moderately lower level of physical function than comparably aged women without a cancer history. Factors associated with higher levels of physical functioning were similar in both groups.

A comparison of acetate and digital templating for hip resurfacing.

This study sought to determine whether templating for metal-on-metal hip resurfacing is more accurate with digital or acetate methodology. The medical records of 102 consecutive patients who underwent hip resurfacing at our institution were retrospectively reviewed. Records lacking preoperative radiographs that included a magnification-establishing marker were excluded, leaving 78 records for study. Two investigators independently prepared acetate and digital templates of the preoperative radiographs, which had been calibrated to 120% magnification, to predict femoral and acetabular component size. Accuracy was measured by comparing the predicted component sizes to the surgically implanted component sizes. Digital templating was more accurate than acetate templating in predicting hip resurfacing component size when measuring accuracy of templates by the absolute error of predicted component sizes (femoral, P < .001; acetabular, P = .002), and by the prediction of components to +/-1 size difference (femoral, P = .001; acetabular, P = .002). Experience of the templating surgeon did not correlate with templating accuracy for acetate or digital templating. Although acetate templating is often regarded as the "gold standard" in preoperative planning, data from the current study shows that digital technology can be used for accurate preoperative templating prior to hip resurfacing procedures.

Computed tomography pulmonary findings in healthy older adult aspirators versus nonaspirators.

OBJECTIVES/HYPOTHESIS: In previous studies, we consistently found that approximately 30% of asymptomatic healthy older adults silently aspirated liquids during a flexible endoscopic evaluation of swallowing (FEES) and that their aspiration status was stable for the following year. However, no studies have systematically evaluated effects of silent aspiration on lung parenchyma and airways. We used computed tomography (CT) to compare lungs of healthy older adult aspirators versus nonaspirators. We hypothesized that CT images would show pulmonary differences in healthy older adult aspirators versus nonaspirators. STUDY DESIGN: Prospective study. METHODS: Fifty healthy older adults (25 aspirators and 25 nonaspirators) who participated in a previous FEES were randomly selected. CT scans were performed; on inspiration, lung views were taken at 1.25 mm and 2.5 mm windows, and on expiration, lung views were taken at 2.5 mm. CT scans were reviewed by radiologists blinded to group assignment. Outcomes included bronchiectasis, bronchiolectasis, bronchial wall thickening, parenchymal band, fibrosis, air trapping, intraluminal airway debris, and tree-in-bud pattern. RESULTS: χ(2) analyses between aspirators and nonaspirators found no statistically significant differences between aspirators and nonaspirators for any outcomes (P > .05). Logistic regression analyses adjusted for smoking did not change the results. CONCLUSIONS: There were no differences in pulmonary CT findings between healthy older adult aspirators and nonaspirators. This study adds to the evidence that some aspiration may be within the range of normal for older adults, or at least does not contribute to a change in pulmonary appearance on CT images. LEVEL OF EVIDENCE: 3b.

Self-renewal and differentiation capacity of urine-derived stem cells after urine preservation for 24 hours.

Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20-54 years old). About 6 × 10(4) cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a "rice grain" shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis.

Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults.

BACKGROUND: Physical function declines, and markers of inflammation increase with advancing age, even in healthy persons. Microbial translocation (MT) is the systemic exposure to mucosal surface microbes/microbial products without overt bacteremia and has been described in a number of pathologic conditions. We hypothesized that markers of MT, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source of chronic inflammation in older persons and be associated with poorer physical function. METHODS: We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire), and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60-89 years), healthy (no evidence of acute or chronic illness) men and women. RESULTS: LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index. sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker. CONCLUSIONS: In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.

Factors influencing bolus dwell times in healthy older adults assessed endoscopically.

OBJECTIVES/HYPOTHESIS: Scant data exist on normal bolus dwell time assessed during flexible endoscopic evaluation of swallowing (FEES). The purpose of this study was to examine bolus dwell time in healthy older adults. Because it has been previously reported that some healthy older adults aspirate, we also sought to determine if bolus dwell time varied as a function of aspiration status. STUDY DESIGN: Prospective. METHODS: Seventy-six healthy volunteers from the seventh, eighth, and ninth decades of life participated. Dwell times were analyzed via FEES as a function of pharyngeal location, liquid type, delivery method, purée type, viscosity, age, and gender. RESULTS: Longer dwell times were evidenced with the eldest participants, straw delivery, and the smallest volume. Adults in the ninth decade were 4.8 (P = .01) and 3.8 (P = .02) times more likely to have longer dwell times at the vallecula and 7.1 (P = .002) and 3.8 (P = 0.02) at the pyriform sinus than those in the seventh and eighth decades, respectively. Longer dwell times at the vallecula and pyriform sinuses were 2 and 2.38 times (P < .0001) more likely for straw than cup delivery, respectively. Boluses of 5 mL were 1.5 times (P < .05) more likely to result in longer dwell times than larger volumes. Bolus dwell times did not significantly differ as a function of aspiration status. CONCLUSIONS: Advanced age, straw delivery, and small volumes yielded longer dwell times. These variables should be considered before diagnosing an abnormal bolus dwell time in elder patients.

The relationship of aspiration status with tongue and handgrip strength in healthy older adults.

BACKGROUND: Recently, subclinical aspiration has been identified in approximately 30% of community-dwelling older adults. Given that the tongue is a key component of the safe swallow, we hypothesized healthy older adults who aspirate will generate less tongue strength than adults who do not aspirate. Furthermore, as muscle weakness may reflect a global effect of aging, we further investigated whether tongue strength is correlated with handgrip strength. METHODS: We assessed 78 healthy community-dwelling older adults (M = 77.3 years, SD = 7.26) for aspiration status (37% aspirators) via flexible endoscopic evaluation of swallowing. Maximal isometric anterior and posterior tongue strength, anterior and posterior swallowing tongue strength, and maximum handgrip strength were measured. RESULTS: Isometric tongue strength was significantly lower in aspirators versus nonaspirators (p = .03) at both the anterior (463 vs 548 mmHg, respectively) and posterior lingual locations (285 vs 370 mmHg, respectively). Likewise, swallowing tongue strength was significantly lower in aspirators versus nonaspirators at both the anterior (270 vs 317 mmHg, respectively) and posterior lingual locations (220 vs 267 mmHg, respectively). There was no difference between aspirators and nonaspirators' handgrip strength (p > .05), although handgrip strength was correlated with posterior tongue strength (r = .34, p = .005). CONCLUSIONS: Lower anterior and posterior isometric and swallowing tongue strength were dependent on aspiration status. Lower lingual strength in healthy adults may predispose them to aspiration. The correlation between tongue and handgrip strength is consistent with the hypothesis that impaired oropharyngeal strength reflects global age-related declines in muscle strength.

Factors influencing aspiration during swallowing in healthy older adults.

OBJECTIVES/HYPOTHESIS: Although flexible endoscopic evaluation of swallowing (FEES) is an established diagnostic tool, little data exist on the effects of varying liquid types on the swallowing outcomes in healthy older adults. STUDY DESIGN: Prospective. METHODS: Seventy-six healthy older adult volunteers participated (i.e., 18, 28, and 30 volunteers in the 7th, 8th, and 9th decades of life, respectively). The effects of age, sex, liquid type (i.e., water, skim, 2% milk, or whole milk), delivery method (i.e., cup or straw), and volume (i.e., 5, 10, 15, or 20 mL) on Penetration Aspiration Scale (PAS) scores were assessed during FEES. RESULTS: Penetration and silent aspiration were observed in 83% and 28% of the participants, respectively. This represented 19% and 3% of participants' 2,432 swallows, respectively. Liquid type (P = .0001), bolus volume (P = .02), and delivery method (P = .04) significantly affected PAS scores. PAS scores were significantly (P < .05) greater for milk versus water swallows, whole- versus skim-milk swallows, 10- and 20-mL versus 5-mL volumes, and straw versus cup delivery. The risk for aspiration increased by approximately two-, three-, and seven-fold with maximal increases in bolus volume, fat content of liquids, and age, respectively. CONCLUSIONS: Occasional aspiration may be an underappreciated phenomenon during FEES in healthy older adults. In addition, milk yielded a higher likelihood of aspiration than water. Accordingly, different liquid types, bolus volumes, and delivery methods should be used to ensure an accurate assessment of aspiration status in healthy older adults.

The effect of incisional negative pressure therapy on wound complications after acetabular fracture surgery.

The purpose of the study was to determine if the use of incisional negative pressure therapy affected the rate of wound complications after acetabular fracture surgery. Between August 1996 to April 2005, 301 patients were found to have had an operatively treated acetabular fracture. There were 235 patients who had placement of incisional vacuum-assisted closure (VAC) who had three (1.27%) deep wound infections and one (0.426%) wound dehiscence. There were 66 consecutive patients who were available in the 5 years preceding the usage of the incisional VAC who had four (6.06%) deep wound infections and two (3.03%) wound dehiscences. This is less than the published infection rate of 4% for patients undergoing operative treatment of acetabular fractures and less than the authors' rate of 6.15% in the time period before the use of the incisional negative pressure wound therapy (p=.0414). The use of incisional negative pressure wound therapy significantly decreases perioperative wound complications after acetabular fracture surgery.

Dynamics of dendritic cell maturation are identified through a novel filtering strategy applied to biological time-course microarray replicates.

BACKGROUND: Dendritic cells (DC) play a central role in primary immune responses and become potent stimulators of the adaptive immune response after undergoing the critical process of maturation. Understanding the dynamics of DC maturation would provide key insights into this important process. Time course microarray experiments can provide unique insights into DC maturation dynamics. Replicate experiments are necessary to address the issues of experimental and biological variability. Statistical methods and averaging are often used to identify significant signals. Here a novel strategy for filtering of replicate time course microarray data, which identifies consistent signals between the replicates, is presented and applied to a DC time course microarray experiment. RESULTS: The temporal dynamics of DC maturation were studied by stimulating DC with poly(I:C) and following gene expression at 5 time points from 1 to 24 hours. The novel filtering strategy uses standard statistical and fold change techniques, along with the consistency of replicate temporal profiles, to identify those differentially expressed genes that were consistent in two biological replicate experiments. To address the issue of cluster reproducibility a consensus clustering method, which identifies clusters of genes whose expression varies consistently between replicates, was also developed and applied. Analysis of the resulting clusters revealed many known and novel characteristics of DC maturation, such as the up-regulation of specific immune response pathways. Intriguingly, more genes were down-regulated than up-regulated. Results identify a more comprehensive program of down-regulation, including many genes involved in protein synthesis, metabolism, and housekeeping needed for maintenance of cellular integrity and metabolism. CONCLUSIONS: The new filtering strategy emphasizes the importance of consistent and reproducible results when analyzing microarray data and utilizes consistency between replicate experiments as a criterion in both feature selection and clustering, without averaging or otherwise combining replicate data. Observation of a significant down-regulation program during DC maturation indicates that DC are preparing for cell death and provides a path to better understand the process. This new filtering strategy can be adapted for use in analyzing other large-scale time course data sets with replicates.

Interleukin-15 receptor-directed immunotoxins atteunuate disease severity in rat adjuvant arthritis.

We previously constructed two Pseudomonas exotoxin (PE)-based immunotoxins, IL15-PEDelta293 (IT1) and IL15M-PEDelta293 (IT2), for eliminating interleukin-15 receptor (IL-15R)-overexpressing cells. These two immunotoxins were generated by fusing either wild-type human IL-15 or an antagonist mutant IL-15 (IL-15M) to a modified form of PE. In this study the anti-arthritic effect of IT1 and IT2 was investigated using the rat model of adjuvant arthritis (AA). We found that both IT1 and IT2 could specifically target IL-15R-positive cells and induce apoptosis. After AA induction, treatment with either IT1 or IT2 resulted in profound improvement of the disease, with reductions in levels of synovial mononuclear leukocytes and certain inflammatory factors. Clinical and histological comparisons, together with the analyses of mRNA expression and the signal transducer and activator of transcription-3 (STAT-3) phosphorylation, revealed that the two immunotoxins decreased joint inflammation in AA rats to a similar extent. These data suggest that eliminating IL-15R-bearing cells via immunotoxins may be a promising approach for RA treatment. In addition, wild-type IL-15-based immunotoxins can be as effective as antagonist mutant IL-15-based immunotoxins in preventing joint inflammation associated with rheumatoid arthritis.

Food avoidance and food modification practices of older rural adults: association with oral health status and implications for service provision.

PURPOSE: Dietary variation is important for health maintenance and disease prevention among older adults. However, oral health deficits impair ability to bite and chew foods. This study examines the association between oral health and foods avoided or modified in a multiethnic rural population of older adults. It considers implications for nutrition and medical service provision to this population. DESIGN AND METHODS: In-home interviews and oral examinations were conducted with 635 adults in rural North Carolina counties with substantial African American and American Indian populations. Avoidance and modification data were obtained for foods representing different dental challenges and dietary contributions. Data were weighted to census data for ethnicity and sex. Bivariate analyses of oral health measures and foods avoided used chi-square and logistic regression tests. Multivariable analyses used proportional odds or nominal regression models. RESULTS: Whole fruits and raw vegetables were the most commonly avoided foods; substantial proportions of older adults also avoided meats, cooked vegetables, and other foods. Food avoidance was significantly associated with self-rated oral health, periodontal disease, bleeding gums, dry mouth, having dentures, and having fewer anterior and posterior occlusal contacts. Associations persisted when controlling for demographic and socioeconomic status indicators. From 24% to 68% of participants reported modifying specific fruits, vegetables, and meats. Modifying harder foods was related to location of teeth and periodontal disease and softer foods to oral pain and dry mouth. IMPLICATIONS: Food services for older adults should consider their oral health status. Policy changes are needed to provide oral health care in benefits for older adults.

Chronic inflammation is associated with low physical function in older adults across multiple comorbidities.

BACKGROUND: Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status. METHODS: We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP); and anthropometric measures. RESULTS: Higher levels of CRP and IL-6, but not TNF-alpha, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results. CONCLUSIONS: Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.