Predicting oxygen uptake for men and women with moderate to severe chronic obstructive pulmonary disease

OBJECTIVE: To develop regression equations for estimating peak oxygen consumption (Vo(2)) for men and women with moderate to severe chronic obstructive pulmonary disease (COPD) from the 6-minute walk test (6MWT). DESIGN: Multivariate analysis of patient pulmonary function and exercise gas exchange indices to 2 outcomes for the 6MWT (distance ambulated, calculated work [6M(WORK)]). SETTING: A university hospital and clinics. PARTICIPANTS: A total of 124 patients (90 men 34 women; age range, 45\N81y), from the community, with moderate to very severe COPD. Forced expiratory volume in 1 second (FEV(1)) ranged from.70 to 2.79L/min, forced vital capacity (FVC) ranged from 1.73 to 5.77L, and FEV(1)/FVC ranged from 24% to 69%. All patients were in stable condition at the time of testing and were on a stable drug regimen. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pulmonary function testing was completed according to American Thoracic Society criteria. Cycle ergometry with gas exchange, by using a ramp protocol, was completed. The 6MWT was done in the hospital corridor, with distances recorded after each minute. Work capacity by each method was reduced from the normal predicted. RESULTS: Peak oxygen uptake (Vo(2)) averaged 1184+/-302mL/min for men and 860+/-256mL/min for women (58%, 68% of predicted, respectively). Ventilatory reserve was limited at an achieved peak ventilation (Ve) of 79.9%+/-19.1% of predicted. Borg scores for dyspnea and leg fatigue were equivalent for each test modality, with leg fatigue being slightly higher for each gender. 6M(WORK) for the 6MWT was the strongest independent predictor of peak Vo(2) (r=.81, P<.0001), whereas that for distance ambulated was correlated at r equal to.54 (P<.0001). This is a 36% improvement in the variance accounted for by the application of 6M(WORK) as the outcome for the 6MWT. Generalized regression modeling was then used to develop equations for the estimation of peak Vo(2) for the 6MWT. Additional variables included in the model were diffusing capacity of lung for carbon dioxide, FVC, maximal inspiratory pressure, weight (in kilograms), and age, with their appropriate interactions. This derived regression model accounted for 79% on the variance for estimation of peak Vo(2) in the patients studied. CONCLUSION: Peak Vo(2) can be estimated for men and for women by using the generalized equations presented. The calculation of 6M(WORK) is an improvement over distance ambulated as the 6MWT outcome. These data build on the existing body of knowledge for the 6MWT and extend its application for patients with COPD. Knowledge of the peak Vo(2) can be used for patient assessment, serial monitoring, evaluating disability, and as a common index of function across modalities. The calculation of 6M(WORK) outperformed distance ambulated and is easily converted to other indices of caloric expenditure that are commonly used in the laboratory and clinical settings.     

Discriminative stimulus effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys.

Drug discrimination was used to examine the effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys. In diazepam-treated (5.6 mg/kg, p.o.) monkeys discriminating the nonselective BZ antagonist flumazenil (0.32 mg/kg, s.c.), the BZ(1)-selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) substituted for flumazenil. The onset of action of beta-CCt was delayed with a dose of 5.6 mg/kg beta-CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ(1)-selective agonists zaleplon (ED(50) = 0.78 mg/kg) and zolpidem (ED(50) = 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by beta-CCt (1.0-5.6 mg/kg, s.c.), and the effects of zaleplon and zolpidem were also antagonized by flumazenil (0.01-0.32 mg/kg, s.c.). Schild analyses supported the notion of a simple, competitive interaction between beta-CCt and midazolam (slope = -1.08; apparent pA(2) = 5.41) or zaleplon (slope = -1.57; apparent pA(2) = 5.49) and not between beta-CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope = -1.03; apparent pA(2) = 7.45) or zolpidem (slope = -1.11; apparent pA(2) = 7.63). These results suggest that the same BZ receptor subtype(s) mediate(s) the effects of midazolam, zolpidem, and zaleplon under these conditions and that selective binding of BZ ligands does not necessarily confer selective effects in vivo.     

Quality-of-care assessment. II. Outpatient medical care following hospital dismissal after myocardial infarction.

This study was undertaken to compare process and outcome methods of quality assessment of medical care in outpatient office practice. Follow-up care after hospitalization for first acute myocardial infarction was used as the model. One hundred fifty-two patients followed up for a minimum of 2 years comprised the study group. An expert committee of cardiologists and internists in community practice established the process criteria for satisfactory care and predicted outcomes of continuing disability and mortality. Using weighted process criteria and a weighted performance index permitted demonstration of a significant association between process items performed at the first posthospitalization visit and 2-year mortality. A significant association could not be demonstrated between later process of care and outcome at 2 years. The outcome assessment study disclosed that predicted disability and mortality rates compared closely with observed outcomes. However, this method for evaluating the quality of outpatient medical care is weakened because little information is available to provide the basis of prediction of satisfactory outcome rates in complicated cases. Although both the process and outcome methods of quality assessment have short comings, the latter method is recommended because satisfactory outcomes is the essential criterion of quality medical care. Moreover, when process items are not specified outcome assessment maintains the flexibility of individual physician practice. Refinement of satisfactory outcome prediction for common illnesses managed in office practice should be the goal for future studies.     

Platelet monoamine oxidase and phenolsulphotransferase M and P in cancer

Phenolsulphotransferase and monoamine oxidase inactivate a wide range of dietary and endogenous phenols/monoamines by sulphoconjugation and oxidative deamination respectively. In this study, both enzymes were measured in platelets from cancer patients and controls. Of the two variants of phenolsulphotransferase, activity of the P form was normal in all groups. Activity of the M form was, however, significantly less than control values in patients with cancer of the rectum and bowel but not in other cancer patient groups. If this finding reflects enzyme activity elsewhere in the body and is not merely a manifestation of an abnormal platelet population, the deficit could expose affected subjects to the action of potentially carcinogenic dietary phenols. Platelet monoamine oxidase activity was significantly raised in the cancer group as a whole, and in all sub-types investigated apart from breast cancer. The increase in the cancer group as a whole was independent of sex, age, drugs, radiotherapy, smoking or platelet count. Its mechanism and significance are unknown but there may be links with the patients' psychiatric state.     

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

Background

Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.

Methods

Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic‐lethal versus non‐recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset.

Results

Five CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5‐CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic‐lethal progression (P = 6.8 × 10^?6) in the testing dataset. For each unit increase in the score there was a four‐fold increase in risk of metastatic‐lethal events (odds ratio, OR = 4.0, 95%CI = 1.8–14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025).

Conclusions

The DNA methylation score improved upon Gleason sum for predicting metastatic‐lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

     

Use of concurrent pupil dilation assessment to inform interpretation and analysis of fMRI data

Potential contributions of concurrently acquired pupil dilation data to functional magnetic resonance imaging (fMRI) experiments were examined. Sixteen healthy participants completed a working memory task (digit sorting) during measurement of pupil dilation outside the fMRI environment and during concurrent 3T fMRI assessment. Pupil dilation increased parametrically with task difficulty inside and outside the scanner, on a similar time course, suggesting that task demand was similar in both environments. The time course of pupil dilation during digit sorting was similar to the time course of the fMRI signal in the middle frontal gyrus, suggesting that middle-frontal gyrus activity indexed the engagement working memory processes. Incorporating individual differences in pupil dilation improved the sensitivity and specificity of general linear modeling analyses of activity in the middle frontal gyrus, above and beyond standard analytic techniques. Results suggest concurrent pupil dilation during fMRI assessment can help to (1) specify whether task demand is the same inside and outside the fMRI environment, (2) resolve the extent to which fMRI signals reflect different aspects of event-related designs, and (3) explain variation in fMRI data due to individual differences in information processing.