Bay Pines VA Healthcare System

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by an incompletely reversible limitation in airflow. A physiological variable--the forced expiratory volume in one second (FEV1)--is often used to grade the severity of COPD. However, patients with COPD have systemic manifestations that are not reflected by the FEV1. We hypothesized that a multidimensional grading system that assessed the respiratory and systemic expressions of COPD would better categorize and predict outcome in these patients. METHODS: We first evaluated 207 patients and found that four factors predicted the risk of death in this cohort: the body-mass index (B), the degree of airflow obstruction (O) and dyspnea (D), and exercise capacity (E), measured by the six-minute-walk test. We used these variables to construct the BODE index, a multidimensional 10-point scale in which higher scores indicate a higher risk of death. We then prospectively validated the index in a cohort of 625 patients, with death from any cause and from respiratory causes as the outcome variables. RESULTS: There were 25 deaths among the first 207 patients and 162 deaths (26 percent) in the validation cohort. Sixty-one percent of the deaths in the validation cohort were due to respiratory insufficiency, 14 percent to myocardial infarction, 12 percent to lung cancer, and 13 percent to other causes. Patients with higher BODE scores were at higher risk for death; the hazard ratio for death from any cause per one-point increase in the BODE score was 1.34 (95 percent confidence interval, 1.26 to 1.42; P<0.001), and the hazard ratio for death from respiratory causes was 1.62 (95 percent confidence interval, 1.48 to 1.77; P<0.001). The C statistic for the ability of the BODE index to predict the risk of death was larger than that for the FEV1 (0.74 vs. 0.65). CONCLUSIONS: The BODE index, a simple multidimensional grading system, is better than the FEV1 at predicting the risk of death from any cause and from respiratory causes among patients with COPD.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are afflicted by comorbidities. Few studies have prospectively evaluated COPD comorbidities and mortality risk. OBJECTIVES: To prospectively evaluate COPD comorbidities and mortality risk. METHODS: We followed 1,664 patients with COPD in five centers for a median of 51 months. Systematically, 79 comorbidities were recorded. We calculated mortality risk using Cox proportional hazard, and developed a graphic representation of the prevalence and strength of association to mortality in the form of a "comorbidome". A COPD comorbidity index (COPD specific comorbidity test [COTE]) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis. We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the validated BODE index. MEASUREMENTS AND MAIN RESULTS: Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors. Of those, 12 predicted mortality and were integrated into the COTE index. Increases in the COTE index were associated with an increased risk of death from COPD-related (hazard ratio [HR], 1.13; 95% confidence interval, 1.08-1.18; P < 0.001) and non-COPD-related causes (HR, 1.18; 95% confidence interval, 1.15-1.21; P < 0.001). Further, increases in the BODE and COTE were independently associated with increased risk of death. A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death (HR, 2.26-2.68; P < 0.001) in all BODE quartile. CONCLUSIONS: Comorbidities are frequent in COPD and 12 of them negatively influence survival. A simple disease-specific comorbidities index (COTE) helps assess mortality risk in patients with COPD.

Diabetes increases the risk for disorders that predispose individuals to hospitalization, including coronary artery, cerebrovascular and peripheral vascular disease, nephropathy, infection, and lower-extremity amputations. The management of diabetes in the hospital is generally considered secondary in importance compared with the condition that prompted admission. Recent studies (1,2) have focused attention to the possibility that hyperglycemia in the hospital is not necessarily a benign condition and that aggressive treatment of diabetes and hyperglycemia results in reduced mortality and morbidity. The purpose of this technical review is to evaluate the evidence relating to the management of hyperglycemia in hospitals, with particular focus on the issue of glycemic control and its possible impact on hospital outcomes. The scope of this review encompasses adult nonpregnant patients who do not have diabetic ketoacidosis or hyperglycemic crises. For the purposes of this review, the following terms are defined (adapted from the American Diabetes Association [ADA] Expert Committee on the Diagnosis and Classification of Diabetes Mellitus) (3): The prevalence of diabetes in hospitalized adult patients is not known. In the year 2000, 12.4% of hospital discharges in the U.S. listed diabetes as a diagnosis. The average length of stay was 5.4 days (4). Diabetes was the principal diagnosis in only 8% of these hospitalizations. The accuracy of using hospital discharge diagnosis codes for identifying patients with …

OBJECTIVES: Chronic subjective tinnitus is a prevalent condition that causes significant distress to millions of Americans. Effective tinnitus treatments are urgently needed, but evaluating them is hampered by the lack of standardized measures that are validated for both intake assessment and evaluation of treatment outcomes. This work was designed to develop a new self-report questionnaire, the Tinnitus Functional Index (TFI), that would have documented validity both for scaling the severity and negative impact of tinnitus for use in intake assessment and for measuring treatment-related changes in tinnitus (responsiveness) and that would provide comprehensive coverage of multiple tinnitus severity domains. DESIGN: To use preexisting knowledge concerning tinnitus-related problems, an Item Selection Panel (17 expert judges) surveyed the content (175 items) of nine widely used tinnitus questionnaires. From those items, the Panel identified 13 separate domains of tinnitus distress and selected 70 items most likely to be responsive to treatment effects. Eliminating redundant items while retaining good content validity and adding new items to achieve the recommended minimum of 3 to 4 items per domain yielded 43 items, which were then used for constructing TFI Prototype 1.Prototype 1 was tested at five clinics. The 326 participants included consecutive patients receiving tinnitus treatment who provided informed consent-constituting a convenience sample. Construct validity of Prototype 1 as an outcome measure was evaluated by measuring responsiveness of the overall scale and its individual items at 3 and 6 mo follow-up with 65 and 42 participants, respectively. Using a predetermined list of criteria, the 30 best-functioning items were selected for constructing TFI Prototype 2.Prototype 2 was tested at four clinics with 347 participants, including 155 and 86 who provided 3 and 6 mo follow-up data, respectively. Analyses were the same as for Prototype 1. Results were used to select the 25 best-functioning items for the final TFI. RESULTS: Both prototypes and the final TFI displayed strong measurement properties, with few missing data, high validity for scaling of tinnitus severity, and good reliability. All TFI versions exhibited the same eight factors characterizing tinnitus severity and negative impact. Responsiveness, evaluated by computing effect sizes for responses at follow-up, was satisfactory in all TFI versions.In the final TFI, Cronbach's alpha was 0.97 and test-retest reliability 0.78. Convergent validity (r = 0.86 with Tinnitus Handicap Inventory [THI]; r = 0.75 with Visual Analog Scale [VAS]) and discriminant validity (r = 0.56 with Beck Depression Inventory-Primary Care [BDI-PC]) were good. The final TFI was successful at detecting improvement from the initial clinic visit to 3 mo with moderate to large effect sizes and from initial to 6 mo with large effect sizes. Effect sizes for the TFI were generally larger than those obtained for the VAS and THI. After careful evaluation, a 13-point reduction was considered a preliminary criterion for meaningful reduction in TFI outcome scores. CONCLUSIONS: The TFI should be useful in both clinical and research settings because of its responsiveness to treatment-related change, validity for scaling the overall severity of tinnitus, and comprehensive coverage of multiple domains of tinnitus severity.

OBJECTIVE: The purpose of this study was to evaluate safety and clinical efficacy of negative pressure wound therapy (NPWT) compared with advanced moist wound therapy (AMWT) to treat foot ulcers in diabetic patients. RESEARCH DESIGN AND METHODS: This multicenter randomized controlled trial enrolled 342 patients with a mean age of 58 years; 79% were male. Complete ulcer closure was defined as skin closure (100% reepithelization) without drainage or dressing requirements. Patients were randomly assigned to either NPWT (vacuum-assisted closure) or AMWT (predominately hydrogels and alginates) and received standard off-loading therapy as needed. The trial evaluated treatment until day 112 or ulcer closure by any means. Patients whose wounds achieved ulcer closure were followed at 3 and 9 months. Each study visit included closure assessment by wound examination and tracings. RESULTS: A greater proportion of foot ulcers achieved complete ulcer closure with NPWT (73 of 169, 43.2%) than with AMWT (48 of 166, 28.9%) within the 112-day active treatment phase (P = 0.007). The Kaplan-Meier median estimate for 100% ulcer closure was 96 days (95% CI 75.0-114.0) for NPWT and not determinable for AMWT (P = 0.001). NPWT patients experienced significantly (P = 0.035) fewer secondary amputations. The proportion of home care therapy days to total therapy days for NPWT was 9,471 of 10,579 (89.5%) and 12,210 of 12,810 (95.3%) for AMWT. In assessing safety, no significant difference between the groups was observed in treatment-related complications such as infection, cellulitis, and osteomyelitis at 6 months. CONCLUSIONS: NPWT appears to be as safe as and more efficacious than AMWT for the treatment of diabetic foot ulcers.

The 6-min walk distance (6MWD) predicted values have been derived from small cohorts mostly from single countries. The aim of the present study was to investigate differences between countries and identify new reference values to improve 6MWD interpretation. We studied 444 subjects (238 males) from seven countries (10 centres) ranging 40-80 yrs of age. We measured 6MWD, height, weight, spirometry, heart rate (HR), maximum HR (HR(max)) during the 6-min walk test/the predicted maximum HR (HR(max) % pred), Borg dyspnoea score and oxygen saturation. The mean ± sd 6MWD was 571 ± 90 m (range 380-782 m). Males walked 30 m more than females (p < 0.001). A multiple regression model for the 6MWD included age, sex, height, weight and HR(max) % pred (adjusted r² = 0.38; p < 0.001), but there was variability across centres (adjusted r² = 0.09-0.73) and its routine use is not recommended. Age had a great impact in 6MWD independent of the centres, declining significantly in the older population (p < 0.001). Age-specific reference standards of 6MWD were constructed for male and female adults. In healthy subjects, there were geographic variations in 6MWD and caution must be taken when using existing predictive equations. The present study provides new 6MWD standard curves that could be useful in the care of adult patients with chronic diseases.

IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

The 6-min walk distance (6MWD) is used to evaluate the functional capacity of patients with chronic obstructive pulmonary disease (COPD). The change in 6MWD over time and its correlation with changes in spirometry and survival are unclear. Patients (n=198) with severe COPD and 41 age-matched controls were followed for 2 yrs, and anthropometrics, spirometry, 6MWD and comorbidities were measured. The 6MWD decreased in the COPD group from 238 +/- 107 m to 218 +/- 112 m (-26 +/- 37 m x yr(-1)), and increased in the control group from 532 +/- 82 m to 549 +/- 86 m (12 +/- 25 m x yr(-1)). In both groups, there was a poor correlation with changes in forced expiratory volume in one second (FEV1). Nonsurvivors in the COPD group (42%) had a more pronounced change in the 6MWD (-40 versus -22 m x yr(-1)) but a similar change in FEV1 (118 versus 102 mL x yr(-1)). The 6MWD independently predicted survival, after accounting for age, body mass index, FEV1 and comorbidities. In severe chronic obstructive pulmonary disease, the 6-min walk distance predicts mortality better than other traditional markers of disease severity. Its measurement is useful in the comprehensive evaluation of patients with severe disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications. OBJECTIVE: To prospectively evaluate the effectiveness of a long-acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization. DESIGN: Randomized, double-blind study. SETTING: 26 Veterans Affairs medical centers. PATIENTS: 1829 patients with moderate to severe COPD (mean baseline FEV(1), 36% predicted). INTERVENTION: Once-daily tiotropium (18 microg) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators. MEASUREMENTS: The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization. RESULTS: Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, -5.7 percentage points [95% CI, -10.4 to -1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, -3.0 percentage points [CI, -5.9 to -0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates. LIMITATIONS: Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months. CONCLUSIONS: Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD.

Wound dressings containing silver as antimicrobial agents are available in various forms and formulations; however, little is understood concerning their comparative efficacy as antimicrobial agents. Eight commercially available silver-containing dressings, Acticoat 7, Acticoat Moisture Control, Acticoat Absorbent, Silvercel, Aquacel Ag, Contreet F, Urgotol SSD and Actisorb, were tested to determine their comparative antimicrobial effectiveness in vitro and compared against three commercially available topical antimicrobial creams, a non treatment control, and a topical silver-containing antimicrobial gel, Silvasorb. Zone of inhibition and quantitative testing was performed by standard methods using Escherichia coli, Pseudomonas aeruginosa, Streptococcus faecalis and Staphylococcus aureus. Results showed all silver dressings and topical antimicrobials displayed antimicrobial activity. Silver-containing dressings with the highest concentrations of silver exhibited the strongest bacterial inhibitive properties. Concreet F and the Acticoat dressings tended to have greater antimicrobial activity than did the others. Topical antimicrobial creams, including silver sulfadiazine, Sulfamylon and gentamicin sulfate, and the topical antimicrobial gel Silvasorb exhibited superior bacterial inhibition and bactericidal properties, essentially eliminating all bacterial growth at 24 hours. Silver-containing dressings are likely to provide a barrier to and treatment for infection; however, their bactericidal and bacteriostatic properties are inferior to commonly used topical antimicrobial agents.

Objective. The correlation between obesity and deficient wound healing has long been established. This review examines the current literature on the mechanisms involved in obesity-related perioperative morbidity. Methods. A literature search was performed using Medline, PubMed, Cochrane Library, and Internet searches. Keywords used include obesity, wound healing, adipose healing, and bariatric and surgical complications. Results. Substantial evidence exists demonstrating that obesity is associated with a number of postoperative complications. Specifically in relation to wound healing, explanations include inherent anatomic features of adipose tissue, vascular insufficiencies, cellular and composition modifications, oxidative stress, alterations in immune mediators, and nutritional deficiencies. Most recently, advances made in the field of gene array have allowed researchers to determine a few plausible alterations and deficiencies in obese individuals that contribute to their increased risk of morbidity and mortality, especially wound complications. Conclusion. While the literature discusses how obesity may negatively affect health on various of medical fronts, there is yet to be a comprehensive study detailing all the mechanisms involved in obesity-related morbidities in their entirety. Improved knowledge and understanding of obesity-induced physiological, cellular, molecular, and chemical changes will facilitate better assessments of surgical risks and outcomes and create efficient treatment protocols for improved patient care of the obese patient population.

Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers.

The BODE index, which integrates body mass index, airflow limitation (forced expiratory volume in one second), dyspnoea and 6-min walk distance, predicts mortality in chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation (PR) improves some components of BODE. It was hypothesised that changes in BODE may reflect the effects of PR. To test this, participation in PR was offered to 246 patients (BODE quartiles 2-4). The patients were divided as follows: no PR (130 who declined rehabilitation or who dropped out from PR), and PR (116 who completed PR). BODE was determined at entry, after PR, and at 1 and 2 yrs. Other outcomes were: length of stay (LOS) for respiratory-related hospitalisations and mortality. At entry, the two groups had similar age and comorbidity but different BODE. After PR, the BODE improved by 19% and returned to baseline after 2 yrs. The BODE worsened in the no PR group by 4% at 12 months and 18% at 2 yrs. Respiratory mortality at 2 yrs for PR was 7%, compared with 39% for no PR. LOS at 1 yr for COPD decreased 20% in PR, while it increased 25% in no PR. In conclusion, pulmonary rehabilitation participation improves BODE and is associated with better outcomes. The BODE index change after pulmonary rehabilitation provides valuable prognostic information.

RATIONALE: Little is known about the clinical factors associated with the development of lung cancer in patients with chronic obstructive pulmonary disease (COPD), although airway obstruction and emphysema have been identified as possible risk factors. OBJECTIVES: To explore incidence, histologic type, and factors associated with development of lung cancer diagnosis in a cohort of outpatients with COPD attending a pulmonary clinic. METHODS: A cohort of 2,507 patients without initial clinical or radiologic evidence of lung cancer was followed a median of 60 months(30–90). At baseline, anthropometrics, smoking history, lung function,and body composition were recorded. Time to diagnosis and histologic type of lung cancer was then registered. Cox analysis was used to explore factors associated with lung cancer diagnosis. MEASUREMENTS AND MAIN RESULTS: A total of 215 of the 2,507 patients with COPD developed lung cancer (incidence density of 16.7 cases per 1,000 person-years). The most frequent type was squamous cell carcinoma (44%). Lung cancer incidence was lower in patients with worse severity of airflow obstruction. Global Initiative for Chronic Obstructive Lung Disease Stages I and II, older age, lower body mass index,and lung diffusion capacity of carbon monoxide less than 80%were associated with lung cancer diagnosis. CONCLUSIONS: Incidence density of lung cancer is high in outpatients with COPD and occurs more frequently in older patients with milder airflow obstruction (Global Initiative for Chronic Obstructive Lung Disease Stages I and II) and lower body mass index. A lung diffusion capacity of carbon monoxide less than 80% is associated with cancer diagnosis. Squamous cell carcinoma is the most frequent histologic type. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

PURPOSE: The purpose of this study was to examine in listeners with normal hearing and listeners with sensorineural hearing loss the within- and between-group differences obtained with 4 commonly available speech-in-noise protocols. METHOD: Recognition performances by 24 listeners with normal hearing and 72 listeners with sensorineural hearing loss were compared for 4 speech-in-noise protocols that varied with respect to the amount of contextual cues conveyed in the target signal. The protocols studied included the Bamford-Kowal-Bench Speech-in-Noise Test (BKB-SIN; Etymōtic Research, 2005; J. Bench, A. Kowal, & J. Bamford, 1979; P. Niquette et al., 2003), the Quick Speech-in-Noise Test (QuickSIN; M. C. Killion, P. A. Niquette, G. I. Gudmundsen, L. J. Revit, & S. Banerjee, 2004), and the Words-in-Noise test (WIN; R. H. Wilson, 2003; R. H. Wilson & C. A. Burks, 2005), each of which used multitalker babble and a modified method of constants, as well as the Hearing in Noise Test (HINT; M. Nilsson, S. Soli, & J. Sullivan, 1994), which used speech-spectrum noise and an adaptive psychophysical procedure. RESULTS: The 50% points for the listeners with normal hearing were in the 1- to 4-dB signal-to-babble ratio (S/B) range and for the listeners with hearing loss in the 5- to 14-dB S/B range. Separation between groups was least with the BKB-SIN and HINT (4-6 dB) and most with the QuickSIN and WIN (8-10 dB). CONCLUSION: The QuickSIN and WIN materials are more sensitive measures of recognition performance in background noise than are the BKB-SIN and HINT materials.

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is overexpressed in prostate cancer, but the mechanism by which MIF exerts effects on tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by prostate cancer cells regulated tumor cell viability. Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression were increased in both androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells, cell surface of CD74 was only detected in androgen-independent (DU-145) prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in androgen-independent prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased tumor volume and tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145 prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145 prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells. Thus, blocking MIF either at the ligand (MIF) or receptor (CD74) may provide new, targeted specific therapies for androgen-independent prostate cancer.

Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.

Minocycline, a clinically used tetracycline for over 40 years, crosses the blood-brain barrier and prevents caspase up-regulation. It reduces apoptosis in mouse models of Huntington's disease and familial amyotrophic lateral sclerosis (ALS) and is in clinical trial for sporadic ALS. Because apoptosis also occurs after brain and spinal cord (SCI) injury, its prevention may be useful in improving recovery. We analyzed minocycline's neuroprotective effects over 28 days following contusion SCI and found significant functional recovery compared to tetracycline. Histology, immunocytochemistry, and image analysis indicated statistically significant tissue sparing, reduced apoptosis and microgliosis, and less activated caspase-3 and substrate cleavage. Since our original report in abstract form, others have published both positive and negative effects of minocycline in various rodent models of SCI and with various routes of administration. We have since found decreased tumor necrosis factor-alpha, as well as caspase-3 mRNA expression, as possible mechanisms of action for minocycline's ameliorative action. These results support reports that modulating apoptosis, caspases, and microglia provide promising therapeutic targets for prevention and/or limiting the degree of functional loss after CNS trauma. Minocycline, and more potent chemically synthesized tetracyclines, may find a place in the therapeutic arsenal to promote recovery early after SCI in humans.

COPD has a profound impact on daily life, yet remains underdiagnosed and undertreated. We set out to develop a brief, reliable, self-scored questionnaire to identify individuals likely to have COPD. COPD-PS development began with a list of concepts identified for inclusion using expert opinion from a clinician working group comprised of pulmonologists (n = 5) and primary care clinicians (n = 5). A national survey of 697 patients was conducted at 12 practitioner sites. Logistic regression identified items discriminating between patients with and without fixed airflow obstruction (AO, postbronchodilator FEV(1)/FVC < 70%). ROC analyses evaluated screening accuracy, compared scoring options, and assessed concurrent validity. Convergent and discriminant validity were assessed via COPD-PS and SF-12v2 score correlations. For known-groups validation, COPD-PS differences between clinical groups were tested. Test-retest reliability was evaluated in a 20% sample. Of 697 patients surveyed, 295 patients met expert review criteria for spirometry performance; 38% of these (n = 113) had results indicating AO. Five items positively predicted AO (p < 0.0001): breathlessness, productive cough, activity limitation, smoking history, and age. COPD-PS scores accurately classified AO status (area under ROC curve = 0.81) and reliable (r = 0.91). Patients with spirometry indicative of AO scored significantly higher (6.8, SD = 1.9; p< 0.0001) than patients without AO (4.0, SD = 2.3). Higher scores were associated with more severe AO, bronchodilator use, and overnight hospitalization for breathing problems. With the prevalence of COPD in the studied cohort, a score on the COPD-PS of greater than five was associated with a positive predictive value of 56.8% and negative predictive value of 86.4%. The COPD-PS accurately classified physician-reported COPD (AUC = 0.89). The COPD-PS is a brief, accurate questionnaire that can identify individuals likely to have COPD.