Randomized controlled trials in industrial low back pain. Part 3. Subacute/chronic pain interventions.

The most significant costs attributed to settlement of workplace back injury claims are related to chronic low back pain (LBP). Unfortunately, our knowledge of this fact has not led to a reduction of the considerable costs paid out annually by employers and insurers to deal with the chronic pain syndrome. This article is the third in a series of reviews on randomized controlled trials found in the English language medical literature between 1975 and 1993. Of more than 4,000 LBP citations, 35 studies met-the selection criteria of randomization, reasonable concurrent controls and work return comparisons. This review focuses on the 12 studies utilizing nonsurgical interventions for subacute and chronic LBP, including multidisciplinary pain clinics, exercise, cognitive-behavioral strategies, and others. A 26-point quality system was again used to compare the methodologic rigor of each study. The majority of prospective studies investigating return to work after chronic LBP have methodological limitations; additional research is clearly needed to more confidently answer the question of what interventions improve work capacity in patients with chronic LBP.

Randomized controlled trials in industrial low back pain relating to return to work. Part 2. Discogenic low back pain.

The purpose of this review was to determine the efficacy of treatments for discogenic low back pain (LBP) by examining all randomized controlled trials (RCTs) of discogenic LBP published in the English language literature between 1975 and 1993 with "return to work" (RTW) as the end point. From more than 4,000 LBP citations, nearly 600 articles were initially reviewed; 35 studies met our selection criteria. Twenty-two studies were discussed in Part 1 (Acute Interventions) or will be discussed in Part 3 (Chronic Interventions). In this review, of 13 RCTs assessing interventions for LBP with sciatica, 9 were appropriate for their focus on, and radiologic confirmation of, discogenic LBP. The treatments assessed included chemonucleolysis, surgical discectomy, and epidural steroid injection. A 26-point system to assess the quality of methodologic rigor was used for each article. Our literature survey found a need for additional studies comparing surgery, conservative care, epidural steroids, traction, and other approaches to determine their individual effects for RTW after discogenic disease.

Intercorrelations and sources of variability in three mutagenicity assays: a population-based study.

The purpose of this study was to evaluate the intercorrelation between three genetic assays in 112 subjects. The group was pooled from two originally separate but homogeneous subgroups of 56 persons each. Procedures included assays for hprt mutant frequencies, micronuclei in human lymphocytes, and mutations at the glycophorin A (gpa) loci. We found no statistically significant or biologically important intercorrelations among the three biomarkers. We did, however, observe significant correlations between log(e) hprt mutant frequency and cloning efficiency (inverse correlation for these 2 variables), age and log(e) hprt mutant frequency, an inverse relationship between cloning efficiency and age, and an important differential sex effect favoring a greater micronuclei frequency in females than males. No significant correlations between the covariates of interest and glycophorin A variant frequencies NN or NO were observed. Using multivariable linear regression, age was found to account for the majority of the variability in hprt mutant frequency (greater than sex and/or smoking); for micronuclei data, only sex contributed a statistically significant and biologically important proportion to the total variation. We conclude that despite observing no significant intercorrelations between the three assays performed simultaneously from the same individuals in a large population database, a significant correlation between age and hprt mutant frequency and an inverse association between cloning efficiency and hprt do exist; furthermore, we verified the strong differential sex-specific effect on micronucleus frequencies.

Amplification and overexpression of the cyclin D1 gene in head and neck squamous cell carcinoma.

Aims-To determine cyclin D1 gene amplification and expression levels in head and neck squamous cell carcinoma (HNSCC) patients.Methods-Total RNA and genomic DNA were isolated from 40 samples of HNSCC tissue and matched normal tissue and were hybridised with a cyclin D1 cDNA probe. Northern and Southern analyses were used to detect mRNA overexpression and cyclin D1 gene amplification, respectively.Results-15 of the 40 HNSCC samples examined (38%) showed cyclin D1 gene amplification. Of these 15 samples, all 13 from which RNA was available showed increased cyclin D1 expression.Conclusions-HNSCC patients with both amplification and overexpression of the cyclin D1 gene are at greater risk than patients who showed no cyclin D1 gene amplification; amplification and over-expression of the cyclin D1 gene may play an important role in the progression of HNSCC and in clinical outcome.

Do persons living near a uranium processing site have evidence of increased somatic cell gene mutations? A first study.

The objective of this study was to examine if individuals living near a uranium processing site have greater mutagenic damage, as measured by three mutagenicity assays, compared with subjects unexposed to any nuclear facilities. The design was a cross-sectional exploratory analysis of 112 subjects; 56 volunteer residents were from within a 5-mile radius of the Fernald Uranium Processing site and 56 'control' subjects were from a geographically separate area unexposed to any known uranium emissions. The groups were constrained to be similar in age and sex composition. The main outcome measures were three human somatic gene mutation assays consisting of the HPRT T-lymphocyte cloning assay to measure 6-thioguanine resistant lymphocytes; the glycophorin A assay to detect the loss of expression of the M or N allele; and the micronucleus assay as a marker of chromosomal damage. The results showed no statistically significant or quantitatively important differences between groups for all three mutagenicity assays; only the unselected cloning efficiency was statistically significantly different between groups (0.42 +/- 0.16 for the Fernald versus 0.35 +/- 0.12 for the comparison groups). In both groups, age was significantly related to HPRT mutant frequency, with a 1.25% rate of increase in mutant frequencies for each 1-year gain of age in the Fernald group and a 1.12% rate of increase in mutant frequencies for each 1-year gain of age in the comparison group. For the micronucleus data, females had a greater mean micronucleus frequency than males. In addition, smokers had an increased mean ln (natural logarithm) HPRT mutant frequency (3.06 +/- 0.14 for current smokers compared with a mean of 2.72 +/- 0.05 for non-current (i.e. never plus former) smokers). Our results are consistent with the previously reported association between sex type and micronucleus frequency, the known relationship between age and T-lymphocyte cloning efficiency and age and HPRT mutant frequency, and verify the wide inter-subject variability for the latter. Finally, we conclude that at a population level, the relationships between current cigarette use and HPRT mutant frequency, and sex type and micronucleus frequency, are stronger than is the association between geographic proximity to a uranium processing site and mutagenic abnormalities.

Randomized controlled trials in industrial low back pain relating to return to work. Part 1. Acute interventions.

Employers and insurers are interested in being able to use cost-effective interventions for returning injured workers to the workplace. Unfortunately, truly objective information is lacking. The purpose of this and two subsequent review articles was to perform thorough scrutiny and methodologic comparison among all obtainable, published randomized and controlled studies on low back pain (LBP) interventions leading to return to work. The study was confined to English language articles published from 1975 through 1993. Of more than 4,000 LBP citations, more than 500 were chosen for review. Of that number, 35 articles met the selection criteria of randomization, reasonable controls, and work return comparisons. This paper focuses on the 10 articles relating to interventions for acute (less than 4 weeks) LBP, and considers bed rest, exercise, spinal manipulation, back school, and case management. A 26-point quality system was used to compare the methodologic rigor of each article. This literature survey demonstrated the meager scientific foundations on which our industrial rehabilitation programs are based.

Sources of variability in the human lymphocyte micronucleus assay: a population-based study.

The cytokinesis block method was used to examine the intraclass correlation coefficient of the human lymphocyte micronucleus assay, sources of variability, and practical issues regarding the number of samples per subject. Twenty samples of 100 binucleate cells from a single phlebotomy per subject were analyzed (n = 112), using methods to evaluate variance components. The results showed marked intraindividual (sampling error) variation greater than interindividual variation, and no between-group contribution to the total variance. The intraclass correlation was 41.6%, indicating that slightly greater than half of the total variation in micronucleus outcomes was due to error variance (i.e., 58.4%). After adjusting for age, the intraclass correlation coefficient decreased trivially from 41.6% to 39.8%. There was a strong differential gender effect, favoring a greater micronuclei frequency in women. In conclusion, the data suggest that most of the variability in our data set for the micronucleus assay was due to sampling error; a strong differential gender effect favoring females was also verified. Equally important, in terms of practical applications, our analysis of the appropriate number of samples per subject revealed that scoring greater than 1,000 cells (10 determinations per subject) yielded no substantial improvement in statistical sensitivity, compared to the traditional 20 determinations. We suggest that more attention should be directed toward improving the assay's utility, while reducing sampling error.

Is there a valid association between skin tags and colonic polyps: insights from a quantitative and methodologic analysis of the literature.

OBJECTIVE: To assess the reported association between skin tags and colonic polyps and to evaluate the methodologic rigor of the studies. DESIGN AND DATA IDENTIFICATION: English-language literature search using MEDLINE, Index Medicus, and bibliographic reviews of texts and all pertinent articles to perform a quantitative and methodologic analysis of all studies from 1983 (the original publication) assessing the association under study. Eligible studies were independently assessed using explicit methodologic guidelines for validity and generalizability of observational research. Two appraisers independently performed tests for heterogeneity and used meta-analytic methods in an attempt to provide summary estimates of the overall strength of association. MEASUREMENTS AND MAIN RESULTS: Significant statistical heterogeneity across studies indicated sharp differences in the direction and magnitude of the odds ratios for the association between skin tags and colonic polyps (chi-square test of homogeneity = 37.42, 9 degrees of freedom; p < 0.005). This marked disparity prevented meaningful pooling of the individual data. The degree of statistical heterogeneity was not significantly reduced after an analysis of specific subgroups of studies. Limitations potentially responsible for the varying outcomes included lack of blinded ascertainment of clinical information, noncomparability of subjects, differing diagnostic evaluations of the colon, and uncontrolled confounding. In addition, all but one study were performed in a tertiary care setting, seriously limiting the results to the "average" subject seen in primary care settings. CONCLUSION: Methodologic limitations and inconsistencies in study outcomes preclude the aggregation of data necessary to compute a valid and meaningful summary estimate of association. Sufficient variability prevents any consensus regarding the association between skin tags and colonic polyps. In addition, the applicability of the results is limited primarily to subjects seen in tertiary care centers, limiting the overall clinical usefulness of skin tags as "biomarkers" of colonic polyps. Recommendations for further research are provided.

Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials.

Beta-Adrenergic blockers have been considered relatively contraindicated in peripheral arterial disease because of the perceived risk that these drugs could worsen intermittent claudication. Therefore, we conducted a meta-analysis of available randomized controlled trials from the English-language literature to determine whether or not beta-blockers exacerbate intermittent claudication. The primary focus of this analysis was the effect of beta-blockers on exercise duration, measured as walking capacity or endurance time. Outcomes were pooled where appropriate. Of 11 eligible reports, six included 11 individual controlled treatment comparisons that provided data for an analysis of pain-free exercise capacity; no effect size was statistically significant. The pooled effect size for pain-free walking distance was -0.24 (95% confidence interval, -0.62 to 0.14), indicating no significant impairment of walking capacity compared with placebo. Only one study reported that certain beta-blockers were associated with worsening of intermittent claudication. These results strongly suggest that beta-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease. In the absence of other contraindications, beta-blockers can probably be used safely in such patients.

The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects. A randomized controlled trial.

The potential antihypertensive effects after prolonged use of small doses of fish oils remain undefined. Therefore, we conducted a randomized, double-blind, controlled crossover study comparing low doses of n-3 fatty acid supplementation with n-6 fatty acids on blood pressure in 33 subjects with mild hypertension. After a 6-week stabilization period, subjects ingested either 2.04 g/d of n-3 fatty acids or safflower oil (4.8 g/d of linoleic acid) for 12 weeks, then crossed over to the alternative encapsulated oil for another 12 weeks, after a 4-week washout period. All antihypertensive drug therapy had been discontinued. For the combined data, there were significant reductions from pretreatment values for supine diastolic (-2.4 mm Hg) and sitting systolic (-4.1 mm Hg) blood pressure after fish oil; no significant changes occurred after safflower oil control. Compared with safflower oil, fish oil supplementation was associated with a statistically significant reduction in mean supine diastolic blood pressure of 3.7 mm Hg (95% confidence interval, -7.3 and 0.1). Sitting diastolic and mean arterial pressures showed a sequence effect; therefore, only the initial period was used in an analysis of their responses. There were significant decreases from pretreatment values for sitting diastolic (-4.4 mm Hg), mean arterial (-5.1 mm Hg), and systolic (-6.5 mm Hg) blood pressure after fish oil. The differences between groups after the 12-week period remained statistically significant for sitting diastolic and sitting mean arterial blood pressures. No adverse changes were noted in plasma levels of lipid-related measures.

The comparative effects of n-3 and n-6 polyunsaturated fatty acids on plasma fibrinogen levels: a controlled clinical trial in hypertriglyceridemic subjects.

It has previously been shown that fish oil supplementation, compared to olive oil, reduces plasma fibrinogen. Presented here are the results of a randomized, double-blind, crossover controlled trail that compared the effects of dietary n-3 and n-6 fatty acid supplementation on plasma fibrinogen levels in 10 patients with hyperlipoproteinemia types IIb or IV. Plasma fibrinogen levels showed statistically significant reductions during both the fish oil and corn oil treatment periods. Other variables related to hemostasis which showed no significant changes from baseline included tissue plasminogen activator activity and inhibitor, protein C antigen, antithrombin III activity, bleeding time, and platelet counts. These data confirm the two previous reports that fish oil supplementation is associated with reductions in plasma fibrinogen levels, thereby modifying a potential nonlipid risk factor for cardiovascular disease. Unlike previous reports, however, n-6 polyunsaturated fatty acids were also associated with significant reductions in fibrinogen levels. Therefore, it is premature to conclude that the fibrinogen-lowering effects of dietary fish oil are unique to n-3 polyunsaturated fatty acids.

Conservative management of intermittent claudication.

OBJECTIVE: To review the evidence for efficacy of three contemporary treatments for intermittent claudication: pentoxifylline, exercise programs, and smoking cessation. DATA IDENTIFICATION: English-language literature search using MEDLINE, Index Medicus, and bibliographic reviews of major texts and all pertinent articles. STUDY SELECTION: For pentoxifylline, randomized, double-blind controlled trials were selected. For exercise, all controlled trials were selected, because few randomized trials have been done. For smoking cessation, 26 pertinent studies were selected after an exhaustive search. DATA EXTRACTION: Study quality was evaluated; therapeutic efficacy was estimated for pentoxifylline and exercise using meta-analytic techniques. For smoking cessation, all outcomes were determined and described. RESULTS: For pentoxifylline, insufficiently reported data led to marked disparity in effect sizes, preventing a meaningful pooled estimate of effectiveness. The results for exercise therapy suggested that dynamic exercise is beneficial (pooled effect size for pain-free walking distance = 1.03; 95% CI, 0.6 to 1.5; P less than 0.0001). Finally, smoking cessation was associated with a reduced frequency of complications due to progressive disease and improved postoperative graft patency rates. CONCLUSIONS: The limited amount and quality of reported data precluded an overall, reliable estimate of pentoxifylline's efficacy. Structured exercise programs increased pain-free walking distance, and smoking cessation improved postoperative graft patency rates and reduced the complications of peripheral arterial disease.

n-3 fatty acid effects on lipids, lipoproteins, and apolipoproteins at very low doses: results of a randomized controlled trial in hypertriglyceridemic subjects.

Although the hypotriglyceridemic effect of large doses of n-3 fatty acids (n-3 FAs) is well established, the effects of prolonged use of very low doses on lipids, lipoproteins, and apolipoproteins have not been clearly defined. This investigation compares the relative effects of very low, clinically practical doses of n-3 FAs on lipids, lipoproteins, and apolipoproteins in hypertriglyceridemic subjects. Ten subjects received 2.2 g n-3 FAs/d (group 1), seven received 1.1 g n-3 FAs/d (group 2), and eight received olive oil (group 3, placebo control) for 20-wk treatment period. In group 1, both low-density-lipoprotein cholesterol (LDL-C) and LDL-apolipoprotein B concentrations increased significantly from baseline values (28% and 23%, respectively; p less than 0.05) after treatment. Compared with the placebo group, the increase in LDL apolipoprotein B in both fish oil groups was statistically and clinically significant (p less than 0.05). Only minor changes in plasma triglyceride concentrations occurred. The data suggest that very low doses of n-3 FAs may cause potentially adverse increases in LDL-C and LDL-apolipoprotein B concentrations.

The effects of omega-3 polyunsaturated fatty acids on blood pressure: a methodologic analysis of the evidence.

The potentially beneficial blood pressure (BP)-lowering effects of marine omega-3 polyunsaturated fatty acids (omega-3-PUFAs) remain controversial. The objective of this qualitative and quantitative (meta-analysis) analysis was to evaluate the results of all available randomized controlled trials that studied the effect of omega-3-PUFAs on BP response. A comprehensive search of the English literature from 1970 to 1988 disclosed only six randomized controlled investigations out of 22 published reports. Four of these were evaluable and therefore eligible for this analysis. Of these, only one evaluated hypertensive subjects. In two trials, there were statistically significant reductions in BP; the one reporting an investigation of hypertensive subjects showed the greatest reduction. Using established methodologic criteria, the quality of each report was evaluated by independent observers. Following this appraisal, the outcomes of each investigation were reanalyzed and pooled using a meta-analysis. There was no statistically significant difference between the omega-3-PUFA groups and the control groups, possibly because of failure to include hypertensive subjects in all but one trial. Despite the positive effects in two studies, little scientifically valid evidence is available to demonstrate a significant BP-lowering effect of omega-3-PUFAs. Areas needing more attention in future research are identified and methods to improve study designs are suggested.

Effects of modest doses of omega-3 fatty acids on lipids and lipoproteins in hypertriglyceridemic subjects. A randomized controlled trial.

Unlike the well-established hypotriglyceridemic effect of omega-3 fatty acid supplementation, the influence of more clinically tolerable doses on lipoproteins and apolipoproteins is less well characterized. Therefore, we compared the relative effects of modest doses of omega-3 fatty acid supplementation with a corn oil control on lipids, lipoproteins, and apolipoproteins in a randomized, double-blind controlled crossover study. Eight hypertriglyceridemic subjects ingested 4.6 g/d of omega-3 fatty acids or 5.4 g/d of linoleic acid (supplied as corn oil) for 8 weeks, then crossed over to the alternative encapsulated oil for another 8 weeks, following an interposed 4-week wash-out period. Compared with the corn oil control, fish oil supplementation caused a significant reduction in triglyceride levels by a mean of 2.21 mmol/L and increased the high-density lipoprotein cholesterol by a mean of 0.13 mmol/L, associated with a significant rise in the high-density lipoprotein 3 subfraction. Furthermore, there was a significant increase in low-density lipoprotein (LDL) apolipoprotein B levels by a mean of 0.246 g/L. Compared with corn oil, no statistically significant change for LDL cholesterol or other apolipoprotein levels occurred, although LDL cholesterol showed a mild elevation. These data suggest that unlike large doses of omega-3 fatty acids, the hypotriglyceridemic effect of modest amounts of encapsulated fish oil supplementation is unaccompanied by favorable changes in LDL cholesterol or LDL apolipoprotein B levels; the potential therapeutic usefulness of modest doses of dietary fish oil for the treatment of hypertriglyceridemia, therefore, may be limited.

Decision rules and clinical prediction of pneumonia: evaluation of low-yield criteria.

Prediction rules have been recommended for guiding the ordering of diagnostic tests. Such rules can be used to define low-yield criteria (LYC) for the purpose of identifying patients with an extremely low probability of disease and hence discouraging test ordering by the physician on patients meeting LYC. In this study, community hospital emergency department populations of adults (n = 255) and children (n = 78) were evaluated prospectively for the presence of predictive clinical parameters and the physician's estimate of pneumonia prior to obtaining a chest film. We developed LYC and analyzed published LYC for obtaining chest films on patients considered at risk for pneumonia by means of logistic regression, receiver operating characteristics curve, and negative predictive value analyses. We were unable to derive or validate clinically useful LYC to improve on the seasoned clinician's probability estimate of pneumonia. We discuss the inherent limitations in the development and application of LYC that must be understood by those who seek to limit the ordering of chest films by the application of guidelines developed from decision rules.

Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen.

STUDY OBJECTIVE: To assess the effects of ibuprofen on blood pressure control in patients being treated with antihypertensive drugs. DESIGN: Randomized, blinded, placebo-controlled, parallel trial of ibuprofen compared with acetaminophen and with placebo in 3-week treatment periods. SETTING: A general internal medicine clinic at a university hospital. PATIENTS: Forty-five patients with essential hypertension controlled by treatment with at least two antihypertensive drugs were enrolled. Of these, 41 completed the study; treatment was discontinued in 3 of the 15 patients in the ibuprofen group due to breakage of the drug capsules, and after randomization in 1 of the 14 patients in the placebo group due to unstable angina. All 15 patients in the acetaminophen group completed the study. INTERVENTIONS: All previous antihypertensive regimens were continued. During the 3-week treatment, ibuprofen, 400 mg, was administered orally every 8 hours; acetaminophen, 1 g, orally every 8 hours; or placebo, 2 capsules, orally every 8 hours. MEASUREMENTS AND MAIN RESULTS: In the ibuprofen group, the mean increase from baseline after 3 weeks of treatment was significant in the average supine diastolic blood pressure (6.4 mm Hg; 95% confidence interval [CI], 1.05 to 11.75; p = 0.0239); supine mean arterial pressure (6.6 mm Hg; 95% CI, 1.25 to 11.95; p = 0.0205); and sitting mean arterial pressure (5.8 mm Hg; 95% CI, 1.57 to 10.04; p = 0.0123). The mean increase in blood pressure variables in the ibuprofen group was significantly different compared with the mean increase in the variables in the placebo group after 3 weeks of treatment: supine systolic blood pressure (7.1 mm Hg compared with -4.5 mm Hg; 95% CI for the difference in means, 2.5 to 20.6; p = 0.0133); supine diastolic pressure (6.4 mm Hg compared with 0.0; 95% CI for difference in means, 0.87 to 12.4; p = 0.0250); supine mean arterial pressure (6.6 mm Hg compared with -1.5; 95% CI for difference in means, 2.0 to 14.2; p = 0.0110); sitting systolic pressure (6.8 mm Hg compared with -3.7; 95% CI for difference in means, 2.0 to 19.0; p = 0.0169); sitting diastolic pressure (5.3 mm Hg compared with -1.1; 95% CI for difference in means, 0.76 to 12.1; p = 0.0273); and sitting mean arterial pressure (5.8 mm Hg compared with -2.0; 95% CI for difference in means, 1.5 to 14.1; p = 0.0169).(ABSTRACT TRUNCATED AT 400 WORDS)