Chapter 4. European guidelines for the management of chronic nonspecific low back pain.
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Chronic Disease↗
Biomedical subjects
S Reis
Publications and source records attributed to S Reis.
An electronic pressure-meter nociception paw test for mice.
The aim of the present investigation was to describe and validate an electronic mechanical test for quantification of the intensity of inflammatory nociception in mice. The electronic pressure-meter test consists of inducing the animal hindpaw flexion reflex by poking the plantar region with a polypropylene pipette tip adapted to a hand-held force transducer. This method was compared to the classical von Frey filaments test in which pressure intensity is automatically recorded after the nociceptive hindpaw flexion reflex. The electronic pressure-meter and the von Frey filaments were used to detect time versus treatment interactions of carrageenin-induced hypernociception. In two separate experiments, the electronic pressure-meter was more sensitive than the von Frey filaments for the detection of the increase in nociception (hypernociception) induced by small doses of carrageenin (30 microg). The electronic pressure-meter detected the antinociceptive effect of non-steroidal drugs in a dose-dependent manner. Indomethacin administered intraperitoneally (1.8-15 mg/kg) or intraplantarly (30-300 microg/paw) prevented the hypersensitive effect of carrageenin (100 microg/paw). The electronic pressure-meter also detected the hypernociceptive effect of prostaglandin E2 (PGE2; 10-100 ng) in a dose-dependent manner. The hypernociceptive effect of PGE2 (100 ng) was blocked by dipyrone (160 and 320 microg/paw) but not by intraplantar administration of indomethacin (300 microg/paw). The present results validate the use of the electronic pressure-meter as more sensitive than the von Frey filaments in mice. Furthermore, it is an objective and quantitative nociceptive test for the evaluation of the peripheral antinociceptive effect of anti-inflammatory analgesic drugs, which inhibit prostaglandin synthesis (indomethacin) or directly block the ongoing hypernociception (dipyrone).
Analysis of Variance↗
The interaction of the Bcr-Abl tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains.
Bcr-Abl is found in more than 95% of cases with CML. The mechanism of Bcr-Abl-induced transformation is not fully understood. Bcr-Abl is a constitutively active tyrosine kinase with transforming capacity for hematopoietic cells. We demonstrated recently that the Src kinase Hck interacts directly with Bcr-Abl by a kinase-independent mechanism. Moreover, the inhibition of the Hck kinase seems to block some of the transforming effects of Bcr-Abl. To identify the binding domains mediating this interaction of Hck with Bcr-Abl, we co-expressed different plasmid and baculovirus vectors containing mutants or single domains of Bcr-Abl and/or Hck in COS7 and Sf9 cells. At least four independent binding regions for Hck were identified in Bcr-Abl, one in Bcr, one in the region comprising the SH3 and SH2 domain of Abl, one in the SH1 domain of Abl, and one in the C-terminal domain of Abl. In the Hck kinase, deletion of the SH2 and/or the SH3 region abolished binding to Bcr-Abl. In contrast, deletion of the Hck SH1 domain enhanced binding of Hck to Abl and Bcr-Abl. In conclusion, the results indicate that the interaction of Bcr-Abl with Hck is mediated by a novel, complex mechanism that involves multiple domains of Bcr-Abl and the SH2 and SH3 domains of Hck.
Animals↗
The pattern and timing of breathing during incremental exercise: a normative study.
Clinical evaluation of the pattern and timing of breathing during submaximal exercise can be valuable for the identification of the mechanical ventilatory consequences of different disease processes and for assessing the efficacy of certain interventions. Sedentary individuals (60 male/60 female, aged 20-80 yrs) were randomly selected from >8,000 subjects and submitted to ramp incremental cycle ergometry. Tidal volume (VT)/resting inspiratory capacity, respiratory frequency, total respiratory time (Ttot), inspiratory time (TI), expiratory time (TE), duty cycle (TI/Ttot) and mean inspiratory flow (VT/TI) were analysed at selected submaximal ventilatory intensities. Senescence and female sex were associated with a more tachypnoeic breathing pattern during isoventilation. The decline in Ttot was proportional to the TI and TE reductions, i.e. TI/Ttot was remarkably constant across age strata, independent of sex. The pattern, but not timing, of breathing was also influenced by weight and height; a set of demographically and anthropometrically based prediction equations are therefore presented. These data provide a frame of reference for assessing the normality of some clinically useful indices of the pattern and timing of breathing during incremental cycle ergometry in sedentary males and females aged 20-80 yrs.
Adult↗
Derivative spectrophotometry as a tool for the determination of drug partition coefficients in water/dimyristoyl-L-alpha-phosphatidylglycerol (DMPG) liposomes.
The partition coefficients (K(p)) between lipid bilayers of dimyristoyl-L-alpha-phosphatidylglycerol (DMPG) unilamellar liposomes and water were determined using derivative spectrophotometry for chlordiazepoxide (benzodiazepine), isoniazid and rifampicin (tuberculostatic drugs) and dibucaine (local anaesthetic). A comparison of the K(p) values in water/DMPG with those in water/DMPC (dimyristoyl-L-alpha-phosphatidylcholine) revealed that for chlordiazepoxide and isoniazid, neutral drugs at physiological pH, the partition coefficients are similar in anionic (DMPG) and zwitterionic (DMPC) liposomes. However, for ionised drugs at physiological pH, the electrostatic interactions are different with DMPG and DMPC, with the cationic dibucaine having a stronger interaction with DMPG, and the anionic rifampicin having a much larger K(p) in zwitterionic DMPC. These results show that liposomes are a better model membrane than an isotropic two-phase solvent system, such as water-octanol, to predict drug-membrane partition coefficients, as they mimic better the hydrophobic part and the outer polar charged surface of the phospholipids of natural membranes.
Chlordiazepoxide↗
Partition coefficients of beta-blockers in bile salt/lecithin micelles as a tool to assess the role of mixed micelles in gastrointestinal absorption.
The objective of this study was to develop non-invasive spectroscopic methods to quantify the partition coefficients of two beta-blockers, atenolol and nadolol, in aqueous solutions of bile salt micelles and to assess the effect of lecithin on the partition coefficients of amphiphilic drugs in mixed bile salt/lecithin micelles, which were used as a simple model for the naturally occurring mixed micelles in the gastrointestinal tract. The partition coefficients (Kp) at 25.0 +/- 0.1degreesC and at 0.1 M NaCl ionic strength were determined by spectrofluorimetry and by derivative spectrophotometry, by fitting equations that relate molar extinction coefficients and relative fluorescence intensities to the partition constant Kp. Drug partition was controlled by the: (i) drug properties, with the more soluble drug in water (atenolol) exhibiting smaller values of Kp, and with both drugs interacting more extensively in the protonated form; and by (ii) the bile salt monomers, with the dihydroxylic salts producing larger values of Kp for the beta-blockers, and with glycine conjugation of the bile acid increasing the values of Kp for the beta-blockers. Addition of lecithin to bile salt micelles decreases the values of Kp of the beta-blockers. Mixed micelles incorporate hydrophobic compounds due to their large size and the fluidity of their core, but amphiphilic drugs, for which the interactions are predominantly polar/electrostatic, are poorly incorporated in mixed micelles of bile salts/lecithin.
Adrenergic beta-Antagonists↗
Effect of liposomes on the rate of alkaline hydrolysis of indomethacin and acemetacin.
The anti-inflammatory, analgesic, and antipyretic drugs indomethacin (INDO) and acemetacin (ACE), extensively used for the treatment of diseases of degenerative or inflammatory character, exhibit marked gastric irritant action, have low water solubility at neutral pH, and decompose in alkali. Alternative formulations are being investigated to obtain products with lower toxicity and higher stability. Here we examine the effect of liposome charge on the rate of alkaline decomposition of INDO and ACE using micelles as reference. Binding of ACE and INDO to zwitterionic hexadecylphosphocholine (HDPC) micelles and phosphatidylcholine (PC) liposomes was analyzed using a two-phase separation model to quantify the effect of these aggregates on the rate of alkaline degradation. The substrate association constants to HDPC micelles were 1335 and 2192 M(-1) for INDO and ACE, respectively, whereas the corresponding values for PC vesicles were 612 and 3050 M(-1). The difference was attributed to the additional hydrophobicity of ACE. The inhibitory effect of HDPC micelles and PC vesicles was quantified by calculating the ratio between the rate constants in water (k(w)) and in the aggregate (k(m)). The values of the k(w)/k(m) ratios for INDO and ACE in HDPC micelles were, respectively, 80 and 42, and in PC liposomes these ratios were 21 and 3.7, respectively. Positively charged micelles of hexadecyltrimethylammonium chloride (CTAC) and vesicles containing varying proportions of dioctadecyldimethylammonium chloride (DODAC) and PC increase the rate of INDO and ACE alkaline decomposition. Vesicle effects were very sensitive to the DODAC/PC ratio, with rates increasing with the proportion of DODAC. The data were analyzed quantitatively using a pseudophase model with explicit consideration of ion exchange. The calculated second-order rate constants in micelles and vesicles were lower than that in water. The charge density in the liposome necessary to increase the entrapment efficiency and decrease drug decomposition can be modulated, by judicious choice of pH and ionic strength. These manipulations can lead to more stable formulation with increased efficiency in drug entrapment and controlled effects on drug stability.
Hydrogen-Ion Concentration↗
A fast and reliable spectroscopic method for the determination of membrane--water partition coefficients of organic compounds.
Partition coefficients (Kp) between egg yolk phosphatidylcholine multilamellar vesicles and water were determined for two nonsteroidal anti-inflammatory drugs (indomethacin and acemetacin) using two independent methodologies: derivative spectrophotometry and variation of the experimental acidity constant in the presence of increasing vesicle concentration. Second-derivative spectrophotometry allowed for total elimination of background signal effects arising from lipid vesicles, without the need for separation techniques that may disturb equilibrium states. By using a model based on a simple partition, the values of K(T)p can be obtained directly; furthermore, by performing determinations at two different pH values it is possible to calculate partition coefficients for the neutral and negatively charged forms of the drugs (K(AH)p and K(A)p). In the other methodology, values of apparent acidity constants (K(app)) were determined by spectrophotometry at different pH values and different lipid concentrations, and an increase in K(app) with decreasing lipid concentration was observed for both drugs, and from this dependence it was possible to calculate K(AH)p and K(A-)p for each drug. These values were used as a check for those obtained by derivative spectroscopy, which has proven to be a reliable and more expeditious method to obtain K(AH)p and K(A-)p .
Animals↗
Study of partition of nitrazepam in bile salt micelles and the role of lecithin.
The effect of trihydroxy (sodium cholate and sodium glycocholate) and dihydroxy (sodium deoxycholate and sodium glycodeoxycholate) bile salt micelles on the spectrophotometric properties and on the solubility of nitrazepam in aqueous solution, at 25.0 degrees C and at ionic strength 0.1 M in sodium chloride, has been assessed. From the results obtained it was possible to calculate the partition coefficients (Kp) of nitrazepam between aqueous and micellar phases. The partition coefficients of nitrazepam have also been determined in mixed micelles of cholate or deoxycholate with lecithin (egg yolk phosphatidylcholine), which were used as a model of the gastrointestinal tract. Drug partition was found to depend on the bile acid (number of hydroxyl groups and conjugation with glycine), and our data indicate further that addition of lecithin to bile salt micelles decreases the values of the partition coefficients in the mixed micelles at physiological pH.
Bile Acids and Salts↗
Doctor-patient discussions of alternative medicine for back pain.
OBJECTIVE: To document the frequency of conversations about alternative medicine during primary care consultations for back pain in diverse settings. DESIGN: "Exit interview" type patient survey. SETTINGS: General practices in Seattle, Washington; rural Israel; and Birmingham, England. PATIENTS: A convenience sample of 218 adults completing a doctor visit for back pain. MAIN OUTCOME MEASURES: Frequencies of doctor-patient discussions of alternative medicine. RESULTS: Alternative medicine was discussed in a minority of visits (US site 40%, Israel site 37%, UK site 14%, p < 0.05). At each site, patients initiated at least half of the discussions. Users were five to six times more likely to discuss alternative medicine with their doctor than non-users (p < 0.05 for comparison at each site). The percentage of patients who used alternative medicine but left the consultation without discussing it was similar at all sites (US site 17%, Israel site 23%, UK site 15%). CONCLUSIONS: Discussions of alternative medicine occurred in a minority of consultations for back pain although the rate varied considerably by site. Discussions were initiated primarily by patients who use it.
Back Pain↗
Conceptual and practical aspects of clinical practice guidelines in family medicine.
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Evidence-Based Medicine↗
Doctor, there's a fly in my soup! Angiotensin-converting enzyme inhibitors, endogenous opioids and visual hallucinations.
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Aged↗
Trends in medical specialty choice among Israeli medical graduates, 1980-1995.
BACKGROUND: Which medical specialties do Israeli medical graduates choose? Answers to this question can serve as an essential means of evaluating both Israeli medical education and the healthcare system. OBJECTIVES: To determine the distribution of medical specialty choice, its change over time and the possible influence of the medical school on the choice; to study the graduates' gender, gender variability in specialty choice and time trends in both; and to assess the choice of family medicine as a career among the graduates as a group, by medical school, gender, and time trends. METHODS: The study population comprised all graduates of the four medical schools in Israel during 16 years: 1980-1995 inclusive. Data were obtained from the four medical schools, the Israel Medical Association's Scientific Council, and the Ministry of Health. Data allowed for correct identification of two-thirds of the graduates. RESULTS: A total of 4,578 physicians graduated during this period. There was a significant growth trend in the proportion of women graduates from 22.6% in 1980 (lowest: 20.0% in 1981) to 35.3 in 1995 (highest: 41.5% in 1991). Overall, 3,063 physicians (66.8%) started residency and 1,714 (37.4%) became specialists. The four most popular residencies were internal medicine, pediatrics, obstetrics and gynecology, and family medicine. Ten percent of Israeli graduates choose family medicine. CONCLUSIONS: The overall class size in Israel was stable at a time of considerable population change. Women's place in Israeli medicine is undergoing significant change. Family medicine is one of the four most popular residencies. A monitoring system for MSC in Israel is imperative.
Career Choice↗
Determining teaching objectives for the family medicine clerkship in medical school--an Israeli national Delphi survey.
BACKGROUND: Most of the published documents proposing teaching objectives for undergraduate clerkships were prepared by expert bodies. Seldom have the clinical teachers, who are critical to the learning process and to the implementation of the teaching objectives, been the actual proponents of its core content. OBJECTIVE: To develop a national-scale proposal of teaching objectives for the family medicine clerkship in medical school, using a consensus method and the actual, community-based teachers as the expert body. METHODS: The Delphi method was chosen for that purpose. In the first round all 189 family medicine teachers in Israeli medical schools were asked to propose five teaching objectives. In the second round the objectives, which were generated in the first round, were characterized by key words and were sent to the participants as a second round for ranking according to their importance. RESULTS: A total of 116 family medicine teachers (61.38%) responded in the first round and 91 of the 116 (78.5%) in the second round. They formulated 51 teaching objectives listed in order of importance, covering a wide array of themes and including knowledge, attitude and skills objectives. The most important objectives were common problems in primary care, recognition of the biopsychosocial model, and understanding the importance of the doctor-patient relationship. The structure of the list provides a unique insight into the relative importance of each objective in the context of the whole core content of the clerkship. CONCLUSIONS: Constructing a proposal for teaching objectives is feasible using the Delphi method and the field instructors as the selecting body. The process and its results can provide faculty with relevant and important suggestions on the content and structure of the family medicine clerkship.
Clinical Clerkship↗
Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms.
BACKGROUND: After hospitalization for chest pain, women are more likely than men to have normal coronary-artery angiograms. In such women, myocardial ischemia in the absence of clinically significant coronary-artery obstruction has long been suspected. Most methods for the detection of the metabolic effects of myocardial ischemia are highly invasive. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. METHODS: We enrolled 35 women who were hospitalized for chest pain but who had no angiographically significant coronary-artery obstructions and 12 age- and weight-matched control women with no evidence of heart disease. Myocardial high-energy phosphates were measured with 31P-NMR spectroscopy at 1.5 tesla before, during, and after isometric handgrip exercise at a level that was 30 percent of the maximal voluntary grip strength. We measured the change in the ratio of phosphocreatine to ATP during exercise. RESULTS: Seven (20 percent) of the 35 women with chest pain and no angiographically significant stenosis had decreases in the phosphocreatine:ATP ratio during exercise that were more than 2 SD below the mean value in the control subjects without chest pain. There were no significant differences between the two groups with respect to hemodynamic variables at rest and during exercise, risk factors for ischemic heart disease, findings on magnetic resonance imaging and radionuclide perfusion studies of the heart, or changes in brachial flow during the infusion of acetylcholine. CONCLUSIONS: Our results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenoses. The most likely cause is microvascular coronary artery disease.
Adenosine Triphosphate↗
Phenolic acids and derivatives: studies on the relationship among structure, radical scavenging activity, and physicochemical parameters.
The antiradical activity of caffeic acid (1), dihydrocaffeic acid (5), and their corresponding n-alkyl esters was evaluated by using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)) method. Dihydrocaffeic acid (5) was the most potent compound, having an antiradical effect higher than that of (+/-)-alpha-tocopherol, whereas caffeic acid (1) was less efficient. Esterification of the carboxyl group of dihydrocaffeic acid (5) had a dramatic effect on its antiradical potency, but similar effects were not observed for caffeic acid (1) derivatives. The n-alkyl esters of both phenolic series had similar potencies, and their antiradical activities were independent of the alkyl chain length. Dose-dependent scavenger effects were found in both series. Acid-base properties of the compounds, evaluated by using potentiometry and spectrophotometry, showed that the catechol moiety had pK(a2) and pK(a3) values of 9. 24-9.02 and 11.38-10.99 in the dihydrocaffeic series and 8.48-8.24 and 11.38-11.07 in the caffeic series, respectively. Antiradical activity and pK(a) values of the compounds were not related.
Antioxidants↗
Doctor-patient concordance and patient initiative during episodes of low back pain.
Doctor-patient concordance and patient initiative were examined in a prospective network interview study, with telephone follow-up, of a cohort of 100 patients presenting with low back pain to their family physician. The average overall rate of concordance was 60% (95% CI = 53 to 66), with the highest rates for radiographic imaging studies and sick leave. No correlation was found between concordance and patient parameters. Subjects initiated an average of two (95% CI = 1.7 to 2.3) diagnostic or therapeutic procedures, the most common of which were for medications (40%), followed by bed rest (26%) and back school (22%). One out of every six subjects initiated a referral to a complementary therapist. Positive correlation was found between patient initiatives and pain severity (P = 0.022) and disability (P = 0.02). There was a negative correlation between the subjects' initiatives and their belief that the physician understood the cause of their pain and its influence on their life (P = 0.02). Overall, those patients who described more pain or disability sought more types of diagnostic and therapeutic measures, while those who felt they had been understood sought less.
Cohort Studies↗
Patients in Europe evaluate general practice care: an international comparison.
BACKGROUND: Patients' evaluations can be used to improve health care and compare general practice in different health systems. AIM: To identify aspects of general practice that are generally evaluated positively by patients and to compare opinions of patients in different European countries on actual care provision. METHOD: An internationally-validated questionnaire was distributed to and completed by patients in 10 European countries. A stratified sample of 36 practices per country, with at least 1080 patients per country, was included. A set of 23 validated questions on evaluations of different aspects of care was used, as well as questions on age, sex, overall health status, and frequency of visiting the GP. RESULTS: The patient sample included 17,391 patients in 10 different countries; the average response rate was 79% (range = 67% to 89%). In general, patients visiting their general practitioner (GP) were very positive about the care provided. For most of the 23 selected aspects of care more than 80% viewed care as good or excellent; in particular, keeping records confidential, GP listening to patients, time during consultations, and quick services in case of urgent problems were evaluated positively. Patients were relatively negative about organisational aspects of care. The evaluations in different countries were largely similar, with some interesting differences; for instance, service and organisational aspects were evaluated more positively in fee-for-service health systems. CONCLUSIONS: Patients in Europe are positive about general practice but improvements in practice management in some countries are requested. More research is needed to study the complex field of differences in expectations and evaluations between countries with different health systems.
Culture↗