Efficacy, Safety, and Predictors of Intradiscal Methylene Blue Injection for Discogenic Low Back Pain: Results of a Multicenter Prospective Clinical Series.

STUDY DESIGN: Prospective clinical study of intradiscal methylene blue injection for the treatment of lumbar discogenic pain. OBJECTIVE: The objective of this study was to collect information about efficacy, safety, and acceptability of the intervention, gain and burden of outcome measures, and sample size assumptions for a potential following randomized controlled trial (RCT). If the pilot study demonstrates that this treatment is potentially effective and safe, and the methods and procedures used in this study are feasible, a RCT follows. SUMMARY OF BACKGROUND DATA: Low back pain (LBP) is a highly common problem with a lifetime prevalence of more than 70%. A substantial part of chronic LBP is attributable to degenerative changes in the intervertebral disc. A recently published RCT assessing the treatment intradiscal injection of methylene blue for chronic discogenic LBP, showed exceptionally good results. METHODS: Patients were selected on clinical criteria, magnetic resonance imaging, and a positive provocative discogram. The primary outcome measure was mean pain reduction at 6 months. RESULTS: Fifteen consecutive patients with chronic lumbar discogenic pain enrolled in a multicenter prospective case series in two interventional pain treatment centers in the Netherlands. Six months after the intervention, 40% of the patients claimed at least 30% pain relief. In patients who responded, physical function improved and medication use diminished. We observed no procedural complications or adverse events. Predictors for success were Pfirrmann grading of 2 or less and higher quality of life mental component scores. CONCLUSIONS: Our findings of 40% positive respondents, and no complications, give reason to set up a randomized, double-blind, placebo-controlled, trial.

Can we "predict" long-term outcome for ambulatory transcutaneous electrical nerve stimulation in patients with chronic pain?

BACKGROUND: Evidence for effectiveness of transcutaneous electrical nerve stimulation (TENS) is still inconclusive. As heterogeneity of chronic pain patients might be an important factor for this lack of efficacy, identifying factors for a successful long-term outcome is of great importance. METHODS: A prospective study was performed to identify variables with potential predictive value for 2 outcome measures on long term (6 months); (1) continuation of TENS, and (2) a minimally clinical important pain reduction of ≥ 33%. At baseline, a set of risk factors including pain-related variables, psychological factors, and disability was measured. RESULTS: In a multiple logistic regression analysis, higher patient's expectations, neuropathic pain, no severe pain (< 80 mm visual analogue scale [VAS]) were independently related to long-term continuation of TENS. For the outcome "minimally clinical important pain reduction," the multiple logistic regression analysis indicated that no multisited pain (> 2 pain locations) and intermittent pain were positively and independently associated with a minimally clinical important pain reduction of ≥ 33%. CONCLUSION: The results showed that factors associated with a successful outcome in the long term are dependent on definition of successful outcome.

Rational pain management in complex regional pain syndrome 1 (CRPS 1)--a network meta-analysis.

OBJECTIVE: Guidelines for complex regional pain syndrome (CRPS) 1 advocate several substance classes to reduce pain and support physical rehabilitation, but guidance about which agent should be prioritized when designing a therapeutic regimen is not provided. Using a network meta-analytic approach, we examined the efficacy of all agent classes investigated in randomized clinical trials of CRPS 1 and provide a rank order of various substances stratified by length of illness duration. DESIGN: In this study a network meta-analysis was conducted. PATIENTS: The participants of this study were patients with CRPS 1. METHOD: Searches in electronic, previous systematic reviews, conference abstracts, book chapters, and the reference lists of relevant articles were performed. Eligible studies were randomized controlled trials comparing at least one analgesic agent with placebo or with another analgesic and reporting efficacy in reducing pain. Summary efficacy stratified by symptom duration and length of follow-up was computed across all substance classes. Two authors independently extracted data. RESULTS: In total, 16 studies were included in the analysis. Bisphosphonates appear to be the treatment of choice in early stages of CRPS 1. The effects of calcitonin surpass that of bisphosphonates and other substances as a short-term medication in more chronic stages of the illness. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs, and vasodilators showed better long-term pain reduction than placebo. LIMITATION: For some drug classes, only a few studies were available and many studies included a small group of patients. Insufficient data were available to analyze efficacy on disability. CONCLUSION: This network meta-analysis indicates that a rational pharmacological treatment strategy of pain management should consider bisphosphonates in early CRPS 1 and a short-term course of calcitonin in later stages. While most medications showed some efficacy on short-term follow-up, only bisphosphonates, NMDA analogs and vasodilators showed better long-term pain reduction than placebo.

Percutaneous radiofrequency ablation of the splanchnic nerves in patients with chronic pancreatitis: results of single and repeated procedures in 11 patients.

BACKGROUND: Pain is a major problem for chronic pancreatitis (CP) patients. Unfortunately, medical therapy often fails. Endoscopic and surgical treatments are invasive, and results vary. Percutaneous radiofrequency ablation of the splanchnic nerves (RFSN) is a relatively new and minimally invasive procedure for treatment of intractable pain in CP patients. MATERIALS AND METHODS: We retrospectively evaluated 18 RFSN procedures in 11 CP patients, all refractory to analgesics. Five patients underwent a second procedure; two patients underwent a third procedure. NRS pain scores were assessed. Complications, analgesics usage, and length of the pain-free period were recorded. RESULTS: Radiofrequency ablation of the splanchnic nerves was effective in 15/18 interventions. The mean NRS pain score decreased from 7.7 ± 1.0 to 2.8 ± 2.7 (P ≤ 0.001). The pain-free period lasted for a median period of 45 weeks. The effect of repeated interventions was comparable to the initial procedure. One transient side effect was reported. Four patients reported significantly reduced analgesic usage; 4 patients completely stopped their pain medication. CONCLUSION: Radiofrequency ablation of the splanchnic nerves is a minimally invasive, effective procedure for pain relief. After the effect has subsided, RFSN can be successfully repeated. RFSN might become an alternative treatment in a selected group of CP patients. A larger, randomized trial is justified to substantiate these findings.

Comparative effectiveness of antibiotics for uncomplicated urinary tract infections: network meta-analysis of randomized trials.

BACKGROUND: The efficacies and adverse effects of different antibiotics for uncomplicated urinary tract infections (UTIs) have been studied by standard meta-analytic methods using pairwise direct comparisons of antimicrobial treatments: the effects of one treatment are compared to those of either another treatment or placebo. However, for clinical decisions, we need to know the effectiveness of each possible treatment in comparison with all relevant alternatives, not with just one. OBJECTIVES: To compare the efficacies and adverse effects of all relevant antibiotics for UTI treatment simultaneously by performing a network meta-analysis using direct and indirect treatment comparisons. METHODS: Using logistic regression analysis, we performed a network meta-analysis of randomized controlled trials (RCTs) published after 1999 that compared different oral antibiotic or placebo regimens for UTI treatment in general practice or outpatient settings. We looked at five binary outcomes: early clinical, early bacteriological, late clinical and late bacteriological outcomes, as well as adverse effects. Consequently, a ranking of the antibiotic regimens could be composed. RESULTS: Using a network structure, we could compare and rank nine treatments from 10 studies. Overall, ciprofloxacin and gatifloxacin appeared the most effective treatments, and amoxicillin-clavulanate appeared the least effective treatment. In terms of adverse effects, there were no significant differences. DISCUSSION: Network meta-analysis shows some clear efficacy differences between different antibiotic treatments for UTI in women. It provides a useful tool for clinical decision making in everyday practice. Moreover, the method can be used for meta-analyses of RCTs across primary care and beyond.

Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index.

BACKGROUND: The BODE index (including body-mass index, airflow obstruction, dyspnoea, and exercise capacity) was an important contribution to the prognostic assessment of patients with chronic obstructive pulmonary disease (COPD). However, no study has assessed whether the risk of mortality predicted by the BODE index matches the observed mortality in different populations. We assessed the calibration of the BODE index, updated it to improve its calibration, and developed and validated a simplified index for use in primary-care settings. METHODS: We included 232 patients from the Swiss Barmelweid cohort with longstanding and severe COPD and 342 patients from the Spanish Phenotype and Course of COPD cohort study who had had their first hospital admission due to moderate-to-severe COPD. In both cohorts we compared the observed 3-year risk of all-cause mortality with the risk predicted by the BODE index. We then updated the BODE index and developed a simplified ADO index (including age, dyspnoea, and airflow obstruction) from the Swiss cohort, and validated both in the Spanish cohort. FINDINGS: Calibration of the BODE index was poor, with relative underprediction of 3-year risk of mortality by 36% in the Swiss cohort (median predicted risk 21.7% [IQR 12.7-31.7] vs 34.1% observed risk; p=0.013) and relative overprediction by 39% in the Spanish cohort (16.7% [12.7-31.7] vs 12.0%; p=0.035). The 3-year risk of mortality predicted by both the updated BODE (median 10.7% [8.1-13.8]) and ADO indices (11.8% [9.1-14.3]) matched the observed mortality in the Spanish cohort well (p=0.99 and p=0.98, respectively). INTERPRETATION: Both the updated BODE and ADO indices could lend support to the prognostic assessment of patients with COPD in specialised and primary-care settings. Such assessment enhances the targeting of treatments to individual patients. FUNDING: Swiss National Science Foundation; Klinik Barmelweid; Fondo de Investigación Sanitaria Ministry of Health, Spain; Agència d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA; Red RCESP; Fondo de Investigación Sanitaria; Fondo de Investigación Sanitaria; Fundació La Marató de TV3; Novartis Farmacèutica, Spain.

Computer-aided detection in full-field digital mammography in a clinical population: performance of radiologist and technologists.

The purpose of the study was to evaluate the impact of a computer-aided detection (CAD) system on the performance of mammogram readers in interpreting digital mammograms in a clinical population. Furthermore, the ability of a CAD system to detect breast cancer in digital mammography was studied in comparison to the performance of radiologists and technologists as mammogram readers. Digital mammograms of 1,048 consecutive patients were evaluated by a radiologist and three technologists. Abnormalities were recorded and an imaging conclusion was given as a BI-RADS score before and after CAD analysis. Pathology results during 12 months follow up were used as a reference standard for breast cancer. Fifty-one malignancies were found in 50 patients. Sensitivity and specificity were computed before and after CAD analysis and provided with 95% CIs. In order to assess the detection rate of malignancies by CAD and the observers, the pathological locations of these 51 breast cancers were matched with the locations of the CAD marks and the mammographic locations that were considered to be suspicious by the observers. For all observers, the sensitivity rates did not change after application of CAD. A mean sensitivity of 92% was found for all technologists and 84% for the radiologist. For two technologists, the specificity decreased (from 84 to 83% and from 77 to 75%). For the radiologist and one technologist, the application of CAD did not have any impact on the specificity rates (95 and 83%, respectively). CAD detected 78% of all malignancies. Five malignancies were indicated by CAD without being noticed as suspicious by the observers. In conclusion, the results show that systematic application of CAD in a clinical patient population failed to improve the overall sensitivity of mammogram interpretation by the readers and was associated with an increase in false-positive results. However, CAD marked five malignancies that were missed by the different readers.

Calcium scores and matrix Gla protein levels: association with vitamin K status.

BACKGROUND: Vascular calcification in humans is associated with an increased cardiovascular risk. Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor for the activation of uncarboxylated matrix Gla protein (ucMGP). It has been suggested that patients on long-term treatment with vitamin K antagonists develop aortic valve calcifications because of lower levels of circulating MGP. We therefore hypothesized that arterial calcification and a low vitamin K status are associated with ucMGP. To that aim, we measured arterial calcium scores, the osteocalcin ratio (OCR), as a proxy for vitamin K status, and ucMGP. MATERIALS AND METHODS: In 36 hypertensive patients, we determined the Agatston score with computer tomography scans of the abdominal aorta, carotid and coronary arteries. The total calcium score was calculated as the sum of the separate Z-scores. RESULTS: The total calcium Z-score was significantly correlated to age (r = 0.683, P < 0.001), smoking (r = 0.372, P = 0.026), total cholesterol (r = 0.353, P = 0.034), LDL cholesterol (r = 0.490, P = 0.003), triglycerides (r = 0.506, P = 0.002), fasting glucose (r = 0.454, P = 0.005), systolic blood pressure (r = 0.363, P = 0.029) and pulse pressure (r = 0.685, P < 0.001). In multivariate regression analyses, OCR and total calcium score were significantly associated with ucMGP. CONCLUSIONS: We found a positive association of total arterial calcium score and a high OCR (reflecting low vitamin K status) with ucMGP serum levels. This warrants further studies to explore the pathophysiological background of this phenomenon.

Strategies for digital mammography interpretation in a clinical patient population.

Mammography is the basic imaging modality for early detection of breast cancer. The aim of this prospective study was to evaluate the impact of different mammogram reading strategies on the diagnostic yield in a consecutive patient population referred for digital mammography to a hospital. First, the effect of using computer-aided detection (CAD) software on the performance of mammogram readers was studied. Furthermore, the impact of employing technologists as either prereaders or double readers was assessed, as compared to the conventional strategy of single reading by a radiologist. Digital mammograms of 1,048 consecutive patients were evaluated by a radiologist and 3 technologists with and without the use of CAD software. ROC analysis was used to study the effects of the different strategies. In the conventional strategy, an overall area under the curve (AUC) of 0.92 was found, corresponding to a sensitivity of 84% and specificity of 94%. When applying CAD software, the AUCs were similar before and after CAD for all readers (mean of 0.95). Employing technologists in prereading and double reading of mammograms resulted in a mean AUC of 0.91 and 0.96, respectively. In the prereading strategy, the corresponding sensitivity and specificity were 81 and 96%; in the double reading strategy they were 96 and 79%, respectively. Concluding, in this clinical population, systematic application of CAD software by either radiologist or technologists failed to improve the diagnostic yield. Furthermore, employing technologists as double readers of mammograms was the most effective strategy in improving breast cancer detection in daily clinical practice.

Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis.

BACKGROUND: Most patients with chronic obstructive pulmonary disease (COPD) receive inhaled long-acting bronchodilators and inhaled corticosteroids. Conventional meta-analyses established that these drugs reduce COPD exacerbations when separately compared with placebo. However, there are relatively few head-to-head comparisons and conventional meta-analyses focus on single comparisons rather than on a simultaneous analysis of competing drug regimens that would allow rank ordering of their effectiveness. Therefore we assessed, using a network meta-analytic technique, the relative effectiveness of the common inhaled drug regimes used to reduce exacerbations in patients with COPD. METHODS: We conducted a systematic review and searched existing systematic reviews and electronic databases for randomized trials of >/= 4 weeks' duration that assessed the effectiveness of inhaled drug regimes on exacerbations in patients with stable COPD. We extracted participants and intervention characteristics from included trials and assessed their methodological quality. For each treatment group we registered the proportion of patients with >/= 1 exacerbation during follow-up. We used treatment-arm based logistic regression analysis to estimate the absolute and relative effects of inhaled drug treatments while preserving randomization within trials. RESULTS: We identified 35 trials enrolling 26,786 patients with COPD of whom 27% had >/= 1 exacerbation. All regimes reduced exacerbations statistically significantly compared with placebo (odds ratios ranging from 0.71 (95% confidence interval [CI] 0.64 to 0.80) for long-acting anticholinergics to 0.78 (95% CI 0.70 to 0.86) for inhaled corticosteroids). Compared with long-acting bronchodilators alone, combined treatment was not more effective (comparison with long-acting beta-agonists: odds ratio 0.93 [95% CI 0.84 to 1.04] and comparison with long-acting anticholinergics: odds ratio 1.02 [95% CI 0.90 to 1.16], respectively). If FEV1 was 40% predicted. This effect modification was significant for inhaled corticosteroids (P = 0.02 for interaction) and combination treatment (P = 0.01) but not for long-acting anticholinergics (P = 0.46). A limitation of this analysis is its exclusive focus on exacerbations and lack of FEV1 data for individual patients. CONCLUSION: We found no evidence that one single inhaled drug regimen is more effective than another in reducing exacerbations. Inhaled corticosteroids when added to long-acting beta-agonists reduce exacerbations only in patients with COPD with FEV1

Costs and effects of using specialized breast technologists in prereading mammograms in a clinical patient population.

OBJECTIVES: The aim of this study was to assess the costs and effects of using specialized breast technologists in prereading mammograms to reduce the increasing workload of radiologists in daily clinical practice. Mammography is the most widely used imaging modality for early detection and diagnosis of breast cancer. METHODS: A total of 1389 mammograms of consecutive patients were evaluated by two technologists trained in mammogram interpretation. The costs and effects of four different experimental strategies of prereading mammograms by technologists were analyzed by decision analytic modeling and compared with the conventional strategy of standard evaluation by the radiologist on duty. RESULTS: Overall, the employment of technologists in this patient population resulted in a potential time saving up to 73 percent (1019/1389) for the radiologist. No additional false-negative imaging results were found as compared to the conventional strategy. The total diagnostic costs in the conventional strategy were determined at euro150,602. The experimental strategies resulted in cost savings up to 17.2 percent (range, euro122,494-euro139,781). CONCLUSIONS: The employment of technologists in prereading mammograms in a clinical patient population could be effective to reduce the workload of radiologists without jeopardizing the detection of malignancies. Furthermore, diagnostic costs can be reduced considerably.

Prevalence, causes, and consequences of masked hypertension: a meta-analysis.

BACKGROUND: Masked hypertension (MH) is a relatively newly detected condition of which little is known. More information about MH may help to improve overall antihypertensive health care. We aimed to investigate the prevalence, potential causes, and associated consequences of MH. METHODS: We searched published literature using MEDLINE, EMBASE, and the Cochrane database completed with references cited in reviews and original study articles. We restricted our research to articles written in the English, German, French, and Spanish language. Studies were included only when the prevalence of MH was reported, office blood pressure (BP) values were given, and methods of BP measurements were described in detail. All data were extracted independently by two readers with a standardized protocol and data-collection form. RESULTS: The prevalence of MH averaged 16.8% (95% confidence interval 13.0-20.5%). The MH prevalence was 7% for children and 19% for adults. MH prevalences did not differ significantly when determined with self or ambulatory BP measurement (21.1% vs. 16.8%; P = 0.42). Subjects with MH had significantly higher left ventricular mass index (LVMI) values than normotensives (110 vs. 98 g/m2; P < 0.01) but similar values as sustained hypertensives (109 g/m2). In addition, patients with MH were more often smokers than normotensives (mean difference 18%; P < 0.03). CONCLUSIONS: MH strikes about a quarter of the patients who were initially classified as normotensives (based on office BP measurements) and of treated hypertensives. Patients with MH seem to have a similar cardiovascular risk as sustained hypertensives but they may remain undetected. The presence of MH seems to be a matter of a coincidently low office BP value not related to certain subject characteristics although the chance of its presence may be increased by smoking and antihypertensive treatment.

Accuracy of semiautomated analysis of 3D contrast-enhanced magnetic resonance angiography for detection and quantification of aortoiliac stenoses.

OBJECTIVES: We sought to compare reproducibility and accuracy of semiautomated stenosis detection and quantification in 3D contrast-enhanced magnetic resonance angiography (CE-MRA) images with conventional evaluation of 3D CE-MRA in patients with peripheral arterial disease (PAD) by using intra-arterial digital subtraction angiography (IA-DSA) as standard of reference. METHODS: Twenty-five patients with PAD underwent CE-MRA and IA-DSA. Three blinded observers independently evaluated CE-MRA datasets for stenoses in the aortoiliac region using semiautomated computer analysis. Semiautomated measurements were compared with conventional measurements of stenosis on CE-MRA datasets, as measured by 3 other independent observers blinded to all other measurements. Interobserver agreement was quantified using kappa (kappa) and intraclass correlation coefficients (ICCs). Sensitivity and specificity were determined for both semiautomated and conventional measurements. RESULTS: Semiautomated measurements were successful in 124 of the 125 arterial segments. The sensitivity of semiautomated measurements was 89% for all observers; specificity varied between 87% and 89%. For conventional measurements of CE-MRA, sensitivity varied between 79% and 86%; specificity was between 86% and 96%. There was good interobserver agreement between all readers for semiautomated measurements (combined kappa for all 3 observers together = 0.78; ICC = 0.82), as well as for conventional measurements (combined kappa = 0.70; and ICC = 0.83). Differences between ICCs, combined kappa values, and accuracy of both measurements were not significant (all P > 0.05). CONCLUSION: Semiautomated analysis of aortoiliac 3D CE-MRA has the same high accuracy for detection and quantification of stenoses as conventional readings of CE-MRA.

The damping properties of the venous plexus of the heel region of the foot during simulated heelstrike.

The damping mechanisms that are operational in the heel pad during the impact phase of locomotion have the important function to protect the musculo-skeletal system from injuries. How this is achieved is still not fully understood, as is for instance illustrated by the 'heel pad paradox', the observation that in vivo and in vitro experiments yielded widely different results. This paradox could so far only partially be explained. In the light of this paradox, and a previous study by our group, we conjectured that the venous plexus might contribute as a hydraulic shock absorber to the damping properties of the heel pad. To investigate this hypothesis in vivo, heel pads of 11 volunteers were subjected to pendulum impact tests, using velocities of 0.2, 0.4, and 0.6 m/s, and three physiologically different, consecutive conditions: (i) a relatively empty venous plexus, (ii) a congested venous plexus, and (iii) a decongested venous plexus. At congestion, the maximum impact force decreased slightly but significantly by 2.6% at 0.2 m/s and 1.8% at 0.4 m/s. This effect was no longer found at 0.6 m/s. Although these effects are rather small, they confirm the fundamental hypothesis that the venous plexus contributes to the damping properties of the heel pad during walking. It is likely that some underestimation of the effect has occurred.

The intermetatarsal and metatarsal declination angles: geometry as a source of error.

BACKGROUND: The measurements on radiographs of the foot are believed to give an objective impression of foot deformities. In patient management, the outcome of these measurements is one of the factors that the physician takes into consideration. In fact, the radiograph is a projection of three-dimensional structures and is as such liable to a certain amount of distortion. To our knowledge this distortion has not been quantified, although it seems important for the interpretation of the measurements. METHODS: First, mathematical models based on the geometry of standard anteroposterior and lateral radiographs were constructed and analyzed. Then, we simulated radiography with these models on three-dimensional data of metatarsals originating from CT scans of 10 normal volunteers. RESULTS: The distortion of the declination angles of the metatarsals was practically negligible. The intermetatarsal angles were distorted up to 5.4 degrees. The measured angles underestimated the three-dimensional angles. CONCLUSIONS: In interpreting the measurements of the metatarsal declination angles, distortion was not a factor. For intermetatarsal angles variability of distortion was only about one third of the reported interobserver variability, but it may have cumulative effects on the error of measured intermetatarsal angles. Moreover, the theoretical models predicted larger distortions in patients with deformities. In interpretation of angular measurements the physician should be aware of these pitfalls.

Plantar pressure and sole thickness of the forefoot.

BACKGROUND: Based on earlier observations that the forefoot bears the highest plantar pressure at its center, the existence of a functional distal transverse arch in normal feet was denied, and plantar pressure was defined as merely the outcome of loading, surface area, and soft tissue. Although plantar pressure drives the changes in the foot, neither the position nor the behavior of the metatarsals during loading can be derived from plantar pressure alone. In light of this, our goal was to describe the changes in thickness in the sole and the corresponding plantar pressure during loading of the foot. METHODS: We used CT to image the foot of 10 subjects in four postures that were chosen to imitate four phases in the walking cycle. Before imaging we also recorded the plantar pressure with a pressure measuring insole on which the subjects were standing. From the data, the minimal thickness of the sole and the corresponding plantar pressure were derived. RESULTS: With the exception of the sesamoids, the thickness of the sole under the bones of the forefoot increased from lateral to medial. This persisted in all postures. Our pressure readings matched previously reported distributions. CONCLUSIONS: Depending on the point of view concerning the sesamoids, the bony prominences were placed in a geometrical arch; but they did not form a functional arch. The soft tissue underneath the heads kept the metatarsals in place; the soft-tissue thickness reflected the principle of adequate cushioning.

Effect of tube angulation on the measurement of intermetatarsal angles.

We systematically investigated the effect of tube angulation on angular distortion of the anteroposterior radiograph of the foot. Three-dimensional data from the metatarsals originating from computed tomographic scans of ten healthy volunteers were projected onto the supporting surface at various tube angulations to simulate radiography. The distortion of the intermetatarsal angles decreased from 1.2 degrees to 3.5 degrees at 20 degrees tube angulation to 0.4 degrees to 2.7 degrees at 0 degrees tube angulation. The relatively small improvement in angular measurement using 0 degrees instead of 15 degrees tube angulation would not outweigh the adverse effects of changing the standard radiographic technique. Physician awareness of this source of error when planning surgical therapy seems more important.

Is placebo analgesia mediated by endogenous opioids? A systematic review.

This systematic review assesses six experimental studies into the mechanism of placebo analgesia in human subjects suffering from clinical pain or experimentally induced ischaemic arm pain. Due to their sophisticated designs, these studies probably provide the best evidence that placebo analgesia exists. They also indicate that placebo analgesia is mediated by endogenous opiates. However, there seems to be room for additional studies.

Expectations of analgesia do not affect spinal nociceptive R-III reflex activity: an experimental study into the mechanism of placebo-induced analgesia.

The purpose of this study was to investigate whether placebo analgesia is mediated by the release of beta-endorphin. In addition to subjective pain reports, we included an objective physiological parameter of nociception reflected by the opioid sensitive nociceptive R-III reflex. Placebo consisted of strong suggestions of pain relief and an intravenous injection of saline. Forty minutes after placebo, either the opioid antagonist naloxone or saline was administered intravenously without subjects noticing (hidden). Sixty healthy males, aged 18-30 years, voluntarily participated in this study. Subjects were randomized into one of four groups: group 1 received placebo and hidden naloxone, group 2 received hidden naloxone only, group 3 received placebo and hidden saline and group 4 received hidden saline only. Pain was induced by electrical stimulation of the sural nerve and evaluated with a visual analogue scale (VAS). In addition, changes in the magnitude of the nociceptive R-III reflex activity were assessed. We determined to what extent R-III reflex activity and subjective pain reports were decreased by placebo and we investigated whether these placebo-induced changes in reflex activity and subjective pain reports were naloxone reversible. Furthermore, we measured the degree of association between pain relief as measured on VAS and changes in R-III reflex activity. Finally, the role of beta-endorphin was assessed by measuring plasma endorphin levels before and after the administration of placebo. This study could not demonstrate a placebo effect as measured on VAS and R-III responses. The administration of placebo did not appear to have an effect on the release of beta-endorphins. Consistently, the antagonizing effects of naloxone were negligible. A subgroup analysis of those who did show a placebo response as indicated on the VAS did not support the supposition that beta-endorphin is released due to placebo suggestion. It is suggested that intensified stimuli and a more effective procedure to induce placebo analgesia (e.g. conditioning) may produce a proper placebo effect.

Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial.

Preparations based on special extracts of the Ginkgo biloba tree are popular in various European countries. Previous studies have suggested the clinical efficacy of Ginkgo in patients with dementia, cerebral insufficiency, or related cognitive decline. However, most of these studies did not fulfill the current methodologic requirements. We assessed the efficacy of the G. biloba special extract EGb 761 in patients with dementia and age-associated memory impairment in relation to dose and duration of treatment. Our study was a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Study participants were elderly patients with dementia (Alzheimer disease or vascular dementia) or age-associated memory impairment (AAMI). A total of 214 participants, recruited from 39 homes for the elderly in the Netherlands, were randomly allocated to Ginkgo (either 240 mg/d or 160 mg/d) or placebo (0 mg/d). After 12 weeks, the subjects in the two Ginkgo groups were randomized to continued Ginkgo treatment or placebo treatment. Primary outcome measures in this study were the Syndrome Kurz Test (SKT; psychometric functioning), the Clinical Global Impression of change (CGI-2; psychopathology, assessed by nursing staff), and the Nuremberg Gerontopsychological Rating Scale for Activities of Daily Living (NAI-NAA; behavioral functioning). One hundred twenty-three patients received Ginkgo (n=79, 240 and 160 mg/d combined) or placebo (n=44) during the 24-week intervention period. We found no statistically significant differences in mean change of scores between Ginkgo and placebo. The differences were SKT: +0.4 (90% confidence interval [CI] -0.9-1.7); CGI-2: +0.1 (90% CI -0.3-0.4), and NAI-NAA: -0.4 (90% CI -1.9-1.2). A positive difference is in favor of Ginkgo. Neither the dementia subgroup (n=36) nor the AAMI subgroup (n=87) experienced a significant effect of Ginkgo treatment. There was no dose-effect relationship and no effect of prolonged Ginkgo treatment. The trial results do not support the view that Ginkgo is beneficial for patients with dementia or age-associated memory impairment.