Patient preferences for osteoarthritis pain and chronic low back pain treatments in the United States: a discrete-choice experiment.

OBJECTIVE: To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. METHODS: We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. RESULTS: The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. CONCLUSION: A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.

Application of fragment based virtual screening towards inhibition of bacterial N-acetyglucosaminidase$.

A structure-based approach is applied for the development of inhibitors of bacterial N-acetyglucosaminidase (autolysin). Autolysins are enzymes involved in the degradation of peptidoglycan and therefore participate in bacterial cell growth and different lysis phenomena. Several studies indicate that by the inhibition of autolysins, and consequently of bacterial cell division, antibacterial activity can be obtained, thus paving the road to a novel group of therapeutics against human pathogens. As crystal structures of the autolysin E (AtlE)-ligand complexes were obtained in our laboratories, fragment-based virtual screening was the method of choice for the initial studies. Fragment libraries from various databases were merged to increase the number of compounds for the virtual screening. Twenty-four commercially available virtual hits were selected and subjected to quantitative analysis of binding interactions using the surface plasmon resonance technique. Twelve fragments showed fragment-AtlE interactions. For F1, the top hit of the virtual screening, a KD of 228 µM was determined, while other fragments displayed non-stoichiometric binding. Blind docking of potential binders uncovers three possible allosteric sites. Ligands of N-acetyglucosaminidase identified in our study represent valuable information for the further development of AtlE inhibitors, which could in future represent antibacterial agents acting by a novel mode of action.

OCT image atlas of healthy skin on sun-exposed areas.

BACKGROUND: Skin cancer represents the most prevalent type of cancer in the United States. Excision of these lesions can leave significant scarring, and a delay in the diagnosis of malignant melanoma could result in metastasis or death. Therefore, developing technology and criteria to accurately diagnose these cancers is of particular importance to the medical community. While biopsy can lead to scarring and infections, dermoscopy and confocal microscopy offer noninvasive imaging methods but are also limited in their ability to determine tumor depth and margins. Optical coherence tomography (OCT) is a promising imaging method that uses near-infrared light backscattering to image structures underneath the surface of the skin. The purpose of this study is to provide examples of variations across different skin locations and to identify common themes that occur with aging and sun exposure, most notably thinning of the epidermis and loss of a distinct dermal-epidermal junction. METHODS: Optical coherence tomography images were taken using the VivoSight swept-source OCT. Images were taken from a 23-year-old man (Subject 1) and an 89-year-old man (Subject 2), both with Fitzpatrick Skin Type I, who did not have any prior skin conditions. We investigated the regions of the body that represent sun-exposed areas. RESULTS: Results including OCT images taken from 19 predominately sun-exposed areas are shown in Figure 2-Figure 20. CONCLUSION: The 2 sets of images demonstrate the variety that exists within OCT imaging of healthy skin, and thus, a comprehensive understanding of the variation in normal skin imaging using OCT is critical to be able to distinguish and diagnose skin cancers when present.

[Recommendations for treatment of fibromyalgia : Where will we stand in 10 years?] / Leitlinien und EULAR-Empfehlungen für die Behandlung der Fibromyalgie : Wo stehen wir in 10 Jahren?

This article elucidates changes in the recommended diagnostics and therapy of fibromyalgia (FM). The recommendations from major internationally recognized guidelines are compared with the newest recommendations of the European League Against Rheumatism (EULAR) that in contrast to the guidelines surprisingly recommend physical exercise after patient education for all FM patients. The differences between the guidelines and the EULAR recommendations are critically discussed in particular because although the literature referred to in the guidelines was similar, the analysis led to different recommendations. Finally, we try to predict how patients will be treated 10 years from now, for which knowledge from the guidelines and the initial approaches that diagnosed heterogeneity in FM are included. Empirically based questions will drive mechanism-based approaches as opposed to simply reacting to symptoms, in order to meet the challenge of an individual, mechanism-oriented treatment.

Comparison of in silico tools for binding site prediction applied for structure-based design of autolysin inhibitors.

Autolysin E (AtlE) is a bacteriolytic enzyme which plays an important role in division and growth of bacterial cells and therefore represents a promising potential drug target. Its 3D structure has been recently elucidated. We used in silico prediction tools to study substrate or ligand (inhibitor) binding regions of AtlE. We applied several freely available tools and a commercial tool for binding site identification and compared results of the prediction. Calculation time, number of predictions and output data provided by specific software vary according to the different approaches utilized by specific method categories. Despite different approaches, binding sites in similar locations on the protein were predicted. Specific amino acid residues that form these binding sites were predicted as binding residues. The predicted residues, especially those with predicted highest conservation score, could theoretically have catalytic and binding properties. According to our results, we assume that E138, which has the highest conservation score, is the catalytic residue and F161, G162 and Y224, which are also highly conserved, are responsible for substrate binding. Ligands developed with binding specificity towards these residues could inhibit the catalysis and binding of the substrate of AtlE. The molecules with inhibitory potency could therefore represent potential new antibacterial agents.

Differential psychophysiological effects of operant and cognitive behavioural treatments in women with fibromyalgia.

BACKGROUND: Determination of psychophysiological effects of operant behavioural (OBT) and cognitive behavioural treatment (CBT) for fibromyalgia patients. METHODS: One hundred and fifteen female patients randomized to OBT (N = 43), CBT (N = 42), or whole-body infrared heat (IH) (N = 30) were compared before and after group treatment as well as at 6- and 12-month follow-ups using intent-to-treat analysis (12 drop-outs). Thirty matched pain-free controls (CON) served as reference group for the initial psychophysiological analysis. Surface electromyogram (EMG), blood pressure, heart rate (HR) and skin conductance levels (SCL) were continuously recorded during adaptation, baseline, social conflict, mental arithmetic and relaxation tasks. RESULTS: At baseline, fibromyalgia patients showed higher SCL and HR, lower diastolic blood pressure and EMG in comparison to controls. OBT and CBT compared to IH significantly reduced pain intensity [OBT: effect size (ES) = 1.21 CI: 0.71-1.71, CBT: ES = 1.23, CI: 0.72-1.74]. OBT increased diastolic blood pressure [ES = 1.13, CI: 0.63-1.63 and CBT reduced SCL (ES) = -0.66, CI: -1.14-0.18] 12 months after treatment. Both CBT and OBT significantly increased EMG levels (OBT: ES = 0.97, CI: 0.48-1.46, CBT: ES = 1.17, CI: 0.67-1.68). In contrast, the IH group did not show any significant changes in the psychophysiological parameters. CONCLUSION: Increased diastolic blood pressure and decreased pain after OBT suggest a reactivation of baroreflex-mechanisms in fibromyalgia and a normalization of the blood pressure and pain functional relationship. Reduced SCL following CBT may indicate reduced general arousal levels. Increased muscle tension after CBT and OBT suggest a normalization of physical parameters. The reduction in pain seems to be mediated by different psychophysiological processes, providing support for mechanism-based treatments might be indicated for CBT and OBT. WHAT DOES THIS STUDY ADD?: Differential physiological stress responses followed different psychological interventions. While OBT influenced blood pressure by restoring blood pressure-pain interaction, CBT reduced stress-related sudomotor activity. These results implicate specific mediating mechanisms in fibromyalgia suggesting a basis for matching based on specific patient psychophysiological features.

Assessment of patients with chronic pain.

Chronic pain is a public health concern affecting 20-30% of the population of Western countries. Although there have been many scientific advances in the understanding of the neurophysiology of pain, precisely assessing and diagnosing a patient's chronic pain problem is not straightforward or well-defined. How chronic pain is conceptualized influences how pain is evaluated and the factors considered when making a chronic pain diagnosis. There is no one-to-one relationship between the amount or type of organic pathology and pain intensity, but instead, the chronic pain experience is shaped by a myriad of biomedical, psychosocial (e.g. patients' beliefs, expectations, and mood), and behavioural factors (e.g. context, responses by significant others). Assessing each of these three domains through a comprehensive evaluation of the person with chronic pain is essential for treatment decisions and to facilitate optimal outcomes. This evaluation should include a thorough patient history and medical evaluation and a brief screening interview where the patient's behaviour can be observed. Further assessment to address questions identified during the initial evaluation will guide decisions as to what additional assessments, if any, may be appropriate. Standardized self-reported instruments to evaluate the patient's pain intensity, functional abilities, beliefs and expectations, and emotional distress are available, and can be administered by the physician, or a referral for in depth evaluation can be made to assist in treatment planning.

Cognitive-behavioral and operant-behavioral therapy for people with fibromyalgia.

The current article reviews the cognitive-behavioral (CB) and operant-behavioral perspectives on chronic pain and suggests an answer to the question why changes in behaviors, attitudes, and emotions are associated with decreases in pain severity and impact discussing potential psychobiological mechanisms that may underlie cognitive and behavioral techniques. The impact of learning such as classical and operant conditioning in behaviors and physical responses including baroreflex sensitivity (BRS), as well as the influence of cognitions on pain perception and impact will be presented to explain general efficacy of cognitive-behavior therapy (CBT) and operant-behavioral therapy (OBT) in the treatment of people with fibromyalgia (FM) describing some of the limitations of published outcome studies. We discuss advances in moderation and mediation of treatment outcomes. Lastly, we will discuss the need for research that takes into account evidence-based medicine, methods that address treatment responders and non-responders, individual trajectories, how we might advance and refine CBT and OBT, and strategies related to relapse prevention, maintenance, and adherence-enhancement taking advantage of evolving, technological methods of service delivery. We provide recommendations of how to move forward in approaching studies of CBT and OBT efficacy as a function of better understanding of patient characteristics and contextual factors. We advocate for the potential of the CB perspective and principle of learning for all health care providers regardless of discipline or training and will give examples for making more effective the patient-rheumatologist-relationship by using the principles discussed.

Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Opioids for chronic low-back pain.

BACKGROUND: The use of opioids in the long-term management of chronic low-back pain (LBP) appears to be increasing. Despite this trend, the benefits and risks of these medications remain unclear. OBJECTIVES: To determine the efficacy of opioids in adults with chronic LBP. SEARCH STRATEGY: We electronically searched CENTRAL, CINAHL and PsycINFO to May 2006; MEDLINE and EMBASE to May 2007. We supplemented our search by reviewing references in relevant systematic reviews and identified trials. SELECTION CRITERIA: We included randomized or quasi-randomized controlled trials assessing the use of opioids (as monotherapy or in combination with other therapies) for longer than four weeks, in adults with chronic LBP. Studies were included if they compared non-injectable opioids to other treatments. Comparisons between opioids were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed methodological quality and extracted data onto a pre-designed form. Results were statistically pooled using RevMan 4.2. We reported on pain and function using standardized mean difference (SMD) with 95% confidence interval (95% CI) and on side effects using absolute risk difference (RD) with 95% CI. MAIN RESULTS: We included four trials. Three compared tramadol to placebo. Pooled results revealed that tramadol was more effective than placebo for pain relief, SMD 0.71 (95% CI 0.39 to 1.02), and improving function, SMD 0.17 (95% CI 0.04 to 0.30). The two most common side effects of tramadol were headaches, RD 9% (95% CI 6% to 12%) and nausea, RD 3% (95% CI 0% to 6%). One trial comparing opioids to another analgesic (naproxen) found opioids were statistically significant for relieving pain but not improving function. When re-calculated, the results were not statistically significant for either pain relief (SMD -0.58; 95% CI -1.42 to 0.26) or improving function (SMD -0.06; 95% CI -0.88 to 0.76) . AUTHORS' CONCLUSIONS: Despite concerns surrounding the use of opioids for long-term management of chronic LBP, there remain few high-quality trials assessing their efficacy. The trials in this review, although achieving high internal validity scores, were characterized by a lack of generalizability, inadequate description of study populations, poor intention-to treat analysis, and limited interpretation of functional improvement. Based on our results, the benefits of opioids in clinical practice for the long-term management of chronic LBP remains questionable. Therefore, further high-quality studies that more closely simulate clinical practice are needed to assess the usefulness, and potential risks, of opioids for individuals with chronic LBP.

An expanded view of psychological aspects in head pain: the biopsychosocial model.

Traditionally, headache has been viewed from a limited perspective, both medically and psychologically. The authors propose that a more expanded view of headache that considers each perspective as important, as embodied in the biopsychosocial model, will greatly enhance understanding and be more useful in treatment planning. This model views pain as emanating from a complex interaction of biological, psychological and social variables. This paper describes the key behavioural, affective and cognitive influences and provides pertinent supporting examples from the literature.

Molecular dynamics of the compensatory response to myocardial infarct.

Myocardial infarct via occlusion of the left anterior descending coronary in rats caused overriding depression in transcription, signal transduction, inflammation and extracellular matrix pathways in the infarct zone within 24 h. In contrast, remote zone gene expression was reciprocally activated during the immediate post-infarct period. Infarct zone signal transduction occurred primarily through TGFbeta1 induction while the remote zone exhibited elevated WNT, NOTCH, GPCR and transmembrane signaling. A minimal day 1 acute phase, inflammatory response was detected in the infarct zone while interleukins (IL1alpha, IL1beta, IL6, IL12alpha, IL18) and the TNFalpha superfamily were activated in the remote zone. Different cytochrome subsets were activated in each left ventricular region on day 1 while anti-oxidant genes were elevated only in the remote zone. The infarct zone exhibited mixed early transcription factor activation across all binding domains with a balance favoring constitutive gene activation and differentiation pathways as opposed to cell proliferation. In contrast, the remote zone exhibited activation of extensive developmental transcription factors involved in specification of cell phenotype, tissue-specific interactions and position-specific cell proliferation on day 1. The day 28 infarct zone response mirrored the day 1 remote zone response including activation of genes associated with matrix remodeling (metallothionein and metalloproteinase 9, 12, 23), as well as genes associated with cell proliferation and phenotype specification (MYC, EGR2, ATF3, HOXA1) recapitulating developmental histogenesis programs.

Oral rehydration solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo controlled study on behalf of the ESPGHAN working group on intestinal infections.

OBJECTIVE: A randomized, double-blind, placebo-controlled multicenter study to evaluate efficacy and safety of a mixture of non-digestible carbohydrates (NDC) as an adjunct to oral rehydration therapy in treatment of acute infectious diarrhea in children with mild to moderate dehydration. METHODS: 144 boys aged 1 to 36 months with diarrhea defined as three or more watery stools per day for >1 day but <5 days with mild or moderate dehydration (World Health Organization criteria) were randomly assigned to receive hypotonic oral rehydration solution (ORS) (Na 60 mmol/L, glucose 111 mmol/L) with or without a mixture of NDC (soy polysaccharide 25%, alpha-cellulose 9%, gum arabic 19%, fructooligosaccharides 18.5%, inulin 21.5%, resistant starch 7%). RESULTS: Intention-to-treat analysis did not show significant differences in mean 48 hour stool volume (ESPGHAN-ORS with NDC versus ESPGHAN-ORS, 140 +/- 124 g/kg versus 143 +/- 114 g/kg; P = 0.41). Duration of diarrhea after randomization was similar in both groups (82 +/- 39 hours versus 97 +/- 76 hours, P = 0.24). There were no significant differences in the duration of hospital stay (111 +/- 44 hours versus 126 +/- 78 hours; P = 0.3). Unscheduled intravenous rehydration was similar in both groups (21.4% versus 16.2%, P = 0.42). CONCLUSION: In boys with acute non-cholera diarrhea with mild to moderate dehydration a mixture of non-digestible carbohydrates was ineffective as an adjunct to oral rehydration therapy.

Types and effectiveness of treatments used by people with chronic pain associated with spinal cord injuries: influence of pain and psychosocial characteristics.

STUDY DESIGN: Postal survey. OBJECTIVES: Because of the high prevalence and inadequate control of pain following spinal cord injury (SCI), it is important to have information about the factors associated with the use of specific pain therapies. We conducted this study to evaluate the ability of pain characteristics and psychosocial factors to predict the use of treatments. SETTING: The Miami Project to Cure Paralysis (Miami, FL, USA). METHODS: People with SCI (n=120) were mailed a packet containing a questionnaire with questions regarding demographic factors, pain characteristics, and pain treatments along with a copy of the Multidimensional Pain Inventory. RESULTS: A total of 59% of the respondents had been prescribed treatment or self-initiated efforts to treat pain over the previous 18-month period. The most common treatments used by this sample were massage (26.6%), opioids (22.5%) and nonsteroidal anti-inflammatory drugs (NSAIDs) (20%). The most effective treatments overall were 'physical therapies' with 50% receiving these treatments indicating that their pain was 'considerably reduced' or that they were 'pain free.' Opioids and anticonvulsants were perceived to be the most effective pharmacological agents prescribed (33.3 and 23.8% reporting their pain was considerably better or eliminated, respectively). People using prescription medication reported significantly greater pain severity, more widespread pain, more descriptive adjectives, more evoked pain, greater difficulty in dealing with pain, and more interference and decreased activity levels due to pain, compared to people not using prescription medication. A combination of greater difficulty in dealing with pain, intense pain, presence of evoked pain, and higher level of perceived support from significant others was predictive of taking prescription medication. CONCLUSION: People taking prescription medication reported significantly more intense pain with neuropathic characteristics that significantly affected daily life and routine activities. A substantial percentage of individuals with pain related to SCI did not obtain significant pain relief from prescription medications. None of the factors assessed predicted the use of nonprescription treatments. The results of this study confirm the inadequacy of available modalities to manage chronic pain related to SCI.

Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: when reaction mechanism is more important than specificity.

We report here that a number of commonly used small peptide caspase inhibitors consisting of a caspase recognition sequence linked to chloromethylketone, fluoromethylketone or aldehyde reactive group efficiently inhibit other cysteine proteases than caspases. The in vitro studies included cathepsins B, H, L, S, K, F, V, X and C, papain and legumain. Z-DEVD-cmk was shown to be the preferred irreversible inhibitor of most of the cathepsins in vitro, followed by Z-DEVD-fmk, Ac-YVAD-cmk, Z-YVAD-fmk and Z-VAD-fmk. Inactivation of legumain by all the inhibitors investigated was moderate, whereas cathepsins H and C were poorly inhibited or not inhibited at all. Inhibition by aldehydes was not very potent. All the three fluoromethylketones efficiently inhibited cathepsins in Jurkat and human embryonic kidney 293 cells at concentrations of 100 microM. Furthermore, they completely inhibited cathepsins B and X activity in tissue extracts at concentrations as low as 1 microM. These results suggest that data based on the use of these inhibitors should be taken with caution and that other proteases may be implicated in the processes previously ascribed solely to caspases.

Insulin effect on leucine kinetics in type 2 diabetes mellitus.

Insulin-induced glucose disposal is impaired in Type 2 diabetes mellitus (T2DM). To determine whether insulin-induced suppression of protein breakdown also is impaired, we measured leucine flux (an index of protein breakdown) in diabetic and nondiabetic subjects during a hyperinsulinemic euglycemic clamp. To avoid the confounding effects of a difference in baseline glucose, glucose concentration in the diabetic subjects was normalized by means of an overnight insulin infusion. Despite higher plasma insulin levels (33.5+/-0.05 vs 132+/-2.7 pmol/l, p<01) diabetic subjects had similar amino acid concentrations and leucine flux (96.9+/-5.8 vs 93.4+/-3.7 micromol/kg/h) as nondiabetic subjects. Infusion of insulin (0.5 mU/kg/min) increased insulin levels (p<0.01) to identical levels in both groups (218+/-16 vs 222+/-19), but the glucose infusion required to maintain euglycemia was higher (p<0.01) in nondiabetic than in diabetic subjects, indicating insulin resistance to glucose disposal in the diabetic subjects. In contrast, leucine flux (81.3+/-4.8 vs 81.6+/-3.4 micromol/kg/h) reached identical levels in both groups. The individual and total amino acid levels also were comparable in both groups. We conclude that suppression of whole body protein turnover in response to an acute increase in insulin is normal in people with T2DM. However, chronic adaptation to high insulin levels occurs, thereby enabling protein breakdown and amino acid concentration to remain within the normal range in people with T2DM.

Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases.

Dipeptidyl peptidase I (DPPI) or cathepsin C is the physiological activator of groups of serine proteases from immune and inflammatory cells vital for defense of an organism. The structure presented shows how an additional domain transforms the framework of a papain-like endopeptidase into a robust oligomeric protease-processing enzyme. The tetrahedral arrangement of the active sites exposed to solvent allows approach of proteins in their native state; the massive body of the exclusion domain fastened within the tetrahedral framework excludes approach of a polypeptide chain apart from its termini; and the carboxylic group of Asp1 positions the N-terminal amino group of the substrate. Based on a structural comparison and interactions within the active site cleft, it is suggested that the exclusion domain originates from a metallo-protease inhibitor. The location of missense mutations, characterized in people suffering from Haim-Munk and Papillon-Lefevre syndromes, suggests how they disrupt the fold and function of the enzyme.

Reliability of the lumbar flexion, lumbar extension, and passive straight leg raise test in normal populations embedded within a complete physical examination.

STUDY DESIGN: The study measured the reliability of the passive straight leg raise (SLR) test and lumbar range of motion (LROM) tests measured as continuous variables embedded within a comprehensive physical examination. OBJECTIVES: To determine the reliability of the SLR and LROM test scores when they are measured with a Cybex electronic inclinometer (Lumex, Inc., New York, NY) within a physical examination. SUMMARY OF BACKGROUND DATA: Good published empirical reliability exists for the Cybex and for SLR and LROM tests when the measurements are taken in isolation from other physical examination procedures. Reliability of the Cybex for continuous SLR and LROM measurement within a physical examination has not been assessed, however. METHODS: Forty-five participants were seen by one of two physician/physiotherapist teams. Participants were examined by both team members. The first examiner conducted the first tests and retested 1 week later (intrarater reliability). The second examined the participants the day after their first appointment (inter-rater reliability). RESULTS: Only two scores showed substantial reliability (defined as r > or = 0.60). These scores were left (r = 0.81) and right (r = 0.79) SLR intrarater reliability. All other scores fell below the specified cutoff. CONCLUSIONS: SLR and LROM scores used clinically are collected during comprehensive physical examinations. Most scores gathered under these conditions were not reliable. These findings have implications for the use of clinically derived SLR and LROM scores.

Intelligent systems for nursing education.

Health care is one of the fastest growing areas in terms of care, treatment and the exploitation of new technology in Slovenia. There is a great need for new approaches ensuring that education and work of health care professionals will be built upon the state of the art in nursing. As a consequence the educational, governmental and "industrial" institutions from Slovenia, UK, Italy and Greece have determined to work on above problem. EU agreed to support the project under the Phare Tempus Framework and the aim of this paper is to present an educational approach based on intelligent systems and its application in nursing education.