Fentanyl vapor self-administration model in mice to study opioid addiction.

Intravenous drug self-administration is considered the "gold standard" model to investigate the neurobiology of drug addiction in rodents. However, its use in mice is limited by frequent complications of intravenous catheterization. Given the many advantages of using mice in biomedical research, we developed a noninvasive mouse model of opioid self-administration using vaporized fentanyl. Mice readily self-administered fentanyl vapor, titrated their drug intake, and exhibited addiction-like behaviors, including escalation of drug intake, somatic signs of withdrawal, drug intake despite punishment, and reinstatement of drug seeking. Electrophysiological recordings from ventral tegmental area dopamine neurons showed a lower amplitude of GABAB receptor-dependent currents during protracted abstinence from fentanyl vapor self-administration. This mouse model of fentanyl self-administration recapitulates key features of opioid addiction, overcomes limitations of the intravenous model, and allows investigation of the neurobiology of opioid addiction in unprecedented ways.

Modular tumor prostheses: are current stem designs suitable for distal femoral reconstruction? A biomechanical implant stability analysis in Sawbones.

INTRODUCTION: High loosening rates after distal femoral replacement may be due to implant design not adapted to specific anatomic and biomechanical conditions. MATERIALS AND METHODS: A modular tumor system (MUTARS®, Implantcast GmbH) was implanted with either a curved hexagonal or a straight tapered stems in eight Sawbones® in two consecutively generated bone defect (10 cm and 20 cm proximal to knee joint level). Implant-bone-interface micromotions were measured to analyze main fixation areas and to characterize the fixation pattern. RESULTS: Although areas of highest relative micromotions were measured distally in all groups, areas and lengths of main fixation differed with respect to stem design and bone defect size. Regardless of these changes, overall micromotions could only be reduced with extending bone defects in case of tapered stems. CONCLUSIONS: The tapered design may be favorable in larger defects whereas the hexagonal may be advantageous in defects located more distally.

Proton beam electron return effect: Monte Carlo simulations and experimental verification.

Proton therapy (PT) is expected to benefit from integration with magnetic resonance (MR) imaging. However, the magnetic field distorts the dose distribution and enhances the dose at tissue-air interfaces by the electron return effect (ERE). The objectives were (a) to provide experimental evidence for the ERE in proton beams and (b) to systematically characterise the dependence of the dose enhancement ratio (DER) on magnetic field strength, orientation, proton energy and voxel size by computer simulations. EBT3 films were irradiated with 200 MeV protons with and without a 0.92 T transverse field of a permanent magnet to determine the DER at effective measurement depths of 0.156 and 0.467 mm from an air interface. High-resolution Monte Carlo simulations were performed to reproduce the irradiation experiments and to calculate the DER for proton energies between 50-200 MeV and magnetic field strengths between 0.35-3 T as function of distance from the air interface. Voxel sizes of 0.05, 0.5 and 1 mm were analysed. DERs of (2.2 ± 0.4)% and (0.5 ± 0.6)% were measured at 0.156 and 0.467 mm from the air interface, respectively. Measurements and simulations agreed within 0.15%. For a 200 MeV proton beam, the maximum DER in 0.05 mm voxels increased with magnetic field strength from 2.6% to 8.2% between 0.35 and 1.5 T, respectively. For a 1.0 T magnetic field, maximum DER increased from 3.2% to 7.6% between 50 and 200 MeV, respectively. Voxel sizes of 0.5 and 1 mm resulted in maximum DER values of 2.6% and 1.4%, respectively. The ERE for proton beams in transverse magnetic fields is measurable. The local dose enhancement is significant, well predictable, decreases rapidly with distance from the air interface, and is negligible beyond 1 mm depth. Its impact on air-filled ionisation chambers and porous tissues (e.g. lung) needs to be considered.

Effects of multilevel surgery on a flexed knee gait in adults with cerebral palsy.

AIMS: A flexed knee gait is common in patients with bilateral spastic cerebral palsy and occurs with increased age. There is a risk for the recurrence of a flexed knee gait when treated in childhood, and the aim of this study was to investigate whether multilevel procedures might also be undertaken in adulthood. PATIENTS AND METHODS: At a mean of 22.9 months (standard deviation 12.9), after single event multi level surgery, 3D gait analysis was undertaken pre- and post-operatively for 37 adult patients with bilateral cerebral palsy and a fixed knee gait. RESULTS: There was a significant improvement of indices and clinical and kinematic parameters including extension of the hip and knee, reduction of knee flexion at initial contact, reduction of minimum and mean knee flexion in the stance phase of gait, improved range of movement of the knee and a reduction of mean flexion of the hip in the stance phase. Genu recurvatum occurred in two patients (n = 3 legs, 4%) and an increase of pelvic tilt (> 5°) was found in 12 patients (n = 23 legs, 31%). CONCLUSION: Adult patients with bilateral cerebral palsy and a flexed knee gait benefit from multilevel surgery including hamstring lengthening. The risk of the occurence of genu recurvatum and increased pelvic tilt is lower than has been previously reported in children. Cite this article: Bone Joint J 2017;99-B:1256-64.

Spinal Cord Injury Pain Instrument and painDETECT questionnaire: Convergent construct validity in individuals with Spinal Cord Injury.

BACKGROUND: Neuropathic pain (NeuP) is a frequent sequel of spinal cord injury (SCI). The SCI Pain Instrument (SCIPI) was developed as a SCI-specific NeuP screening tool. A preliminary validation reported encouraging results requiring further evaluation in terms of psychometric properties. The painDETECT questionnaire (PDQ), a commonly applied NeuP assessment tool, was primarily validated in German, but not specifically developed for SCI and not yet validated according to current diagnostic guidelines. We aimed to provide convergent construct validity and to identify the optimal item combination for the SCIPI. The PDQ was re-evaluated according to current guidelines with respect to SCI-related NeuP. METHODS: Prospective monocentric study. Subjects received a neurological examination according to the International Standards for Neurological Classification of SCI. After linguistic validation of the SCIPI, the IASP-grading system served as reference to diagnose NeuP, accompanied by the PDQ after its re-evaluation as binary classifier. Statistics were evaluated through ROC-analysis, with the area under the ROC curve (AUROC) as optimality criterion. The SCIPI was refined by systematic item permutation. RESULTS: Eighty-eight individuals were assessed with the German SCIPI. Of 127 possible combinations, a 4-item-SCIPI (cut-off-score = 1.5/sensitivity = 0.864/specificity = 0.839) was identified as most reasonable. The SCIPI showed a strong correlation (rsp  = 0.76) with PDQ. ROC-analysis of SCIPI/PDQ (AUROC = 0.877) revealed comparable results to SCIPI/IASP (AUROC = 0.916). ROC-analysis of PDQ/IASP delivered a score threshold of 10.5 (sensitivity = 0.727/specificity = 0.903). CONCLUSION: The SCIPI is a valid easy-to-apply NeuP screening tool in SCI. The PDQ is recommended as complementary NeuP assessment tool in SCI, e.g. to monitor pain severity and/or its time-dependent course. SIGNIFICANCE: In SCI-related pain, both SCIPI and PainDETECT show strong convergent construct validity versus the current IASP-grading system. SCIPI is now optimized from a 7-item to an easy-to-apply 4-item screening tool in German and English. We provided evidence that the scope for PainDETECT can be expanded to individuals with SCI.

Structural changes in the thigh muscles following trans-femoral amputation.

INTRODUCTION: Early ambulation is the principal objective in trans-femoral amputees. Postamputation modifications complicate the rehabilitation process due to a reduced control at the interface between stump and prosthesis. The aim of this study is to determine whether magnetic resonance imaging depicts the amount of fatty degeneration of the thigh muscles after trans-femoral amputation (TFA). METHODS: A total of 12 patients following a TFA on the basis of a bone neoplasm or metastasis with an evaluable postoperative MRI were identified. Using the Goutallier classification, the fatty degeneration of the thigh muscles was analyzed in the middle (M) and at the distal end (E) of the residual limb at T1 (10.6 months) and T2 (25.6 months). RESULTS: Analysis at two different levels showed different grades of fatty degeneration of thigh muscles after TFA at T1 and T2. Comparing fatty degeneration at both levels of the stump, the quadriceps femoris revealed a significant change (p = 0.01) at T1 and M. sartorius and adductor (p = 0.02) at T2. CONCLUSIONS: MRI is an excellent diagnostic tool to evaluate fatty degeneration after TFA. The highest amount of fatty degeneration of the quadriceps muscle was monitored within the first 10 months. Early physiotherapy is important to strengthen the remaining stump muscles during rehabilitation.

[Chronic low back pain and psychological comorbidity : A review]. / Chronische untere Rückenschmerzen und psychische Komorbidität : Eine Übersicht.

BACKGROUND: Back pain is a common, disabling problem in Germany. Previous research has evaluated associations between low back pain (LBP), depression, and fear. OBJECTIVES: The results should provide ideas of how to optimize preventive measures, give guidelines for rehabilitation of patients with LBP, and to develop new therapies. MATERIALS AND METHODS: A systematic review of the literature including primary publications and meta-analyses using set search criteria in PubMed was performed. A meta-analysis was then done. RESULTS: In all, 34 studies met the inclusion and quality criteria, whereby 14 studies were included in the meta-analysis. In the literature, significantly different depression scores were reported for people with LBP compared to a healthy control group. The pain perception in persons with LBP is associated with depression and fear. The correlation between depression and pain perception was highly significant in 5 studies (p < 0.01) and significant in 8 studies (p < 0.05). Fear and pain perception were highly significant in 4 studies (highly significant, p < 0.01) and significant in 3 studies (p < 0.05); 5 studies had no significant results. The studies were very heterogeneous. CONCLUSIONS: The results can improve the understanding of the complexity of LBP perception and its therapy. The generalization of the results is limited. To cover the correlation of psychosocial and lifestyle factors and pain perception of LBP, further research is required. To obtain a clearer picture of pain perception in persons with LBP, standardized pain assessment would be beneficial. In addition, we recommend that future studies follow standardized procedures to allow greater comparability.

Multilevel surgery in adults with cerebral palsy.

AIMS: Single-event multilevel surgery (SEMLS) has been used as an effective intervention in children with bilateral spastic cerebral palsy (BSCP) for 30 years. To date there is no evidence for SEMLS in adults with BSCP and the intervention remains focus of debate. METHODS: This study analysed the short-term outcome (mean 1.7 years, standard deviation 0.9) of 97 ambulatory adults with BSCP who performed three-dimensional gait analysis before and after SEMLS at one institution. RESULTS: Two objective gait variables were calculated pre- and post-operatively; the Gillette Gait Index (GGI) and the Gait Profile Score (GPS). The results were analysed in three groups according to their childhood surgical history (group 1 = no surgery, group 2 = surgery other than SEMLS, group 3 = SEMLS). Improvements in gait were shown by a significant decrease of GPS (p = 0.001). Similar results were obtained for both legs (GGI right side and left side p = 0.01). Furthermore, significant improvements were found in all subgroups although this was less marked in group 3, where patients had undergone previous SEMLS. DISCUSSION: SEMLS is an effective and safe procedure to improve gait in adults with cerebral palsy. However, a longer rehabilitation period is to be expected than found in children. SEMLS is still effective in adult patients who have undergone previous SEMLS in childhood. TAKE HOME MESSAGE: Single-event multilevel surgery is a safe and effective procedure to improve gait disorders in adults with bilateral spastic cerebral palsy.

[Development and content of the behavioral therapy module of the MiSpEx intervention: Randomized, controlled trial on chronic nonspecific low back pain]. / Beschreibung und empirische Fundierung des verhaltenstherapeutischen Moduls der MiSpEx-Intervention: Randomisierte, kontrollierte Studie zu chronischem unspezifischem Rückenschmerz.

Back pain is a complex phenomenon that goes beyond a simple medical diagnosis. The aetiology and chronification of back pain can be best described as an interaction between biological, psychological, and social processes. However, to date, multimodal prevention and intervention programs for back pain that target all three aetiological factors have demonstrated limited effectiveness. This lack of supportive evidence for multimodal programmes in the treatment of back pain could be due to the fact that few programs are suitable for long-term and unsupervised use in everyday life. Moreover, in combining the elements from various therapies, little attention has been paid to the mechanisms underlying the synergistic effects of the separate components. In this contribution, we will describe the development of a new multimodal intervention for back pain that set out to address these limitations. To this end, the biological elements of neuromuscular adaptation is supplemented with cognitive behavioral and psychophysiological techniques in an intervention that can be followed at home as well as in clinics, and that is suitable for all grades of pain. The efficacy of this intervention will be tested in a multicentric randomized controlled longitudinal trial (n = 714) at five time points over a period of 6 months. Here we will describe the development and the content of this new intervention.

Preoperative scoring and limits of prognostication: functional outcome after surgical decompression in metastatic spinal cord compression.

OBJECTIVE: To determine whether preoperative parameters correlate with the postoperative functional outcome in para- and tetraplegic patients with lung, kidney, breast and prostate cancer and metastatic spinal cord compression (MSCC). METHODS: Information on 43 patients undergoing decompressive surgery and rehabilitation for MSCC was reviewed, including primary tumor, age, pre- and postoperative ambulation status, mobility subcategory of the Spinal Cord Injury Measure (mSCIM) and the Tokuhashi score. Differences between groups were analyzed by the nonparametric χ(2) test, and correlation coefficients (Spearman's rho) were computed. RESULTS: Preoperative ambulation (p < 0.001), the American Spinal Injury Association Impairment Scale (p < 0.001) and the type of operation (p = 0.02) influenced the postoperative functional outcome. Any positive change in the mSCIM was influenced by preoperative ambulation (p < 0.001). Patients with breast carcinoma showed significantly more positive changes in the mSCIM compared with other tumors (p = 0.002). No correlation was found between the treatment categories of the Tokuhashi score and the preoperative ambulatory status (p = 0.13) or the change in ambulation status (p = 0.29). CONCLUSION: The postoperative functional outcome of MSCC patients shows a linear association between the categories of the Tokuhashi score and the change in ambulation status. We recommend surgical decompression even in a palliative situation (Tokuhashi score 0-8) with the aim of optimizing the short-term rehabilitation outcome.

Fixation of the shorter cementless GTS™ stem: biomechanical comparison between a conventional and an innovative implant design.

INTRODUCTION: Conventional cementless total hip arthroplasty already shows very good clinical results. Nevertheless, implant revision is often accompanied by massive bone loss. The new shorter GTS™ stem has been introduced to conserve femoral bone stock. However, no long-term clinical results were available for this implant. A biomechanical comparison of the GTS™ stem with the clinically well-established CLS(®) stem was therefore preformed to investigate the targeted stem philosophy. MATERIALS AND METHODS: Four GTS™ stems and four CLS(®) stems were implanted in a standardized manner in eight synthetic femurs. A high-precision measuring device was used to determine micromotions of the stem and bone during different load applications. Calculation of relative micromotions at the bone-implant interface allowed the rotational implant stability and the bending behavior of the stem to be determined. RESULTS: Lowest relative micromotions were detected near the lesser trochanter within the proximal part of both stems. Maximum relative micromotions were measured near the distal tip of the stems, indicating a proximal fixation of both stems. For the varus-valgus-torque application, a comparable stem bending behavior was shown for both stems. CONCLUSION: Both stems seem to provide a comparable and adequate primary stability. The shortened GTS™ design has a comparable rotational stability and bone-implant flexibility compared to a conventional stem. This study demonstrates that the CLS(®) stem and the GTS™ stem exhibit similar biomechanical behavior. However, a clinical confirmation of these experimental results is still required.

The influence of bone marrow- and synovium-derived mesenchymal stromal cells from osteoarthritis patients on regulatory T cells in co-culture.

There is increasing evidence that inflammation in the synovium plays a major role in the progression of osteoarthritis (OA). However, the immunogenic properties of mesenchymal stromal cells (MSCs), which are considered to regulate immunity in various diseases, remain largely unknown in OA. The purpose of this study was to determine the influence of MSCs from OA patients on regulatory T cells (Tregs ) in an allogeneic co-culture model. Bone marrow (BM) and synovial membrane (SM) were harvested from hip joints of OA patients and co-cultured with lymphocytes enriched in CD4(+) CD25(+) CD127(-) regulatory T cells (Treg (+) LC) from healthy donors. Treg proportions and MSC markers were assessed by flow cytometry. Cytokine levels were assessed after 2 and 5 days of co-cultivation. Additionally, Treg (+) LC cultures were analysed in the presence of interleukin (IL)-6 and MSC-supernatant complemented medium. B-MSCs and S-MSCs were able to retain the Treg proportion compared to lymphocyte monocultures. T cell-MSC co-cultures showed a significant increase of IL-6 compared to MSC cultures. S-MSCs produced higher amounts of IL-6 compared to B-MSCs, both in single and T cell co-cultures. The effect of retaining the Treg percentage could be reproduced partially by IL-6 addition to the medium, but could only be observed fully when using MSC culture supernatants. Our data demonstrate that retaining the Treg phenotype in MSC-T cell co-cultures can be mediated by MSC derived from OA patients. IL-6 plays an important role in mediating these processes. To our knowledge, this study is the first describing the interaction of MSCs from OA patients and Tregs in an allogeneic co-culture model.

The effects of muscle-tendon surgery on dynamic electromyographic patterns and muscle tone in children with cerebral palsy.

During multilevel surgery, muscle-tendon lengthening (MTL) is commonly carried out in children with cerebral palsy. However, it is unclear if MTL also modifies increased muscle tone and if pathologic activation patterns are changed as an indirect effect of the biomechanical changes. Since investigations addressing this issue are limited, this study aimed at evaluating the effects of MTL on muscle tone and activation pattern. Forty-two children with spastic diplegia who were treated by MTL underwent standardized muscle tone testing (modified Ashworth and Tardieu test), dynamic EMG and three-dimensional gait analysis before, one and three years after MTL. For the evaluation of muscle activation patterns the norm-distance of dynamic EMG data was analyzed. Range of motion and joint alignment in clinical examination were found to be significantly improved one year after MTL. However, deterioration of these parameters was noted after three years. Muscle tone was significantly reduced one year postoperatively but showed an increase after three years. Joint kinematics were found significantly closer to reference data of age matched controls initially after surgery, but deteriorated until three years postoperatively. However, the EMG patterns of the muscles which were surgically addressed were found to be unchanged in either follow-up. These findings suggest that despite the influence of MTS on biomechanics and physiology (muscle tone reduction and improvements of joint mobility and gait pattern) MTS does not change abnormal patterns of muscle activation. Recurrence of increased muscle tone and deterioration of kinematic parameters three years after surgery may be attributed to these persistent pathologic activation patterns.

Motion capture of the upper extremity during activities of daily living in patients with spastic hemiplegic cerebral palsy.

Investigations using motion capture to analyze limitations in range of motion (ROM) of the upper extremity in adults with cerebral palsy (CP) are scarce. To evaluate the influence of those limitations on activities of daily living (ADL) and to determine potential mechanisms of compensation, we investigated 15 adults with hemiplegic CP using motion capture while they performed 10 defined ADLs. Data from the nonaffected body side and those from an age-matched able-bodied group were also collected and compared with our subjects. We measured motion of the elbow, shoulder, and trunk and found significant differences in ROM at these sites. The most pronounced reduction in ROM was observed distally in supination and pronation of the elbow. Here, the affected body side of the adults showed a reduction in supination of 45° compared to the able-bodied group. Furthermore we found a correlation between the Manual Ability Classification System (MACS) and the limitations in ROM. In summary, adults with spastic, hemiplegic CP show limitations in ROM accentuated distally during ADLs. The MACS gives conclusive information about those limitations.

The effect of polytrauma as a possible confounder in the outcome of monotraumatic vs polytraumatic paraplegic patients: a clinical cohort study.

STUDY DESIGN: Clinical cohort study. OBJECTIVE: To evaluate if the impact of the severity of the trauma as a possible confounding factor influences the neurological and functional recovery in paraplegia during the course of a 6-month follow-up period after injury. SETTING: Spinal Cord Injury Center, Heidelberg University Hospital, Germany. METHODS: A retrospective monocentric analysis, from 2002 to 2008, of the Heidelberg European Multicenter Study about spinal cord injury database was performed. We included 31 paraplegic patients (neurological level T1-T12) who were assigned either to a monotrauma (polytraumaschluessel (PTS) 1) or to a polytrauma (PTS≥2) group. The American Spinal Injury Association Impairment Scale, lower extremity motor score, pin prick, light touch and the spinal cord independence measure (SCIM) were obtained at five distinct time points after trauma. Data were analyzed using Mann-Whitney U-test (α<0.05). RESULTS: The changes in lower extremity motor score, pin prick and light touch showed no significant differences in both groups over the whole evaluation period. Polytraumatic paraplegics showed a significantly delayed increase of SCIM between 2 and 6 weeks compared with monotraumatic patients, followed by a quantitative increase in the subitems bladder management, bowel management, use of toilet and prevention of pressure sores between 3 and 6 months (P=0.031). The mean length of primary rehabilitation in the polytrauma group was 5.5 vs 3.6 months in monotrauma. CONCLUSIONS: The prognosis of polytraumatic paraplegics in terms of neurological recovery is not inferior to those with monotrauma. Multiple-injured patients need a prolonged hospital stay to reach the functional outcome of monotraumatic patients.

[Collagen hydroxyapatite (Healos) saturated with gentamicin or levofloxacin. In vitro antimicrobial effectiveness - a pilot study]. / Mit Gentamicin oder Levofloxacin gesättigter Kollagenhydroxyapatit (Healos). Antimikrobielle In-vitro-Wirksamkeit - eine Pilotstudie.

BACKGROUND: The functions of synthetic bone graft substitutes include not only structural support to provide bone healing and osseous ingrowth but also the ability to serve as a local antibiotic delivery system to prevent or treat infections of the spine. MATERIAL AND METHODS: The impregnation and antibiotic efficiency of gentamicin and levofloxacin with Healos was investigated in vitro and compared with Healos without an antibiotic additive. These antibiotic-loaded bone graft substitutes were examined without dilution and with 10-fold and 100-fold dilution for activity against spondylodiscitis-causing bacteria on different agar plates using an agar diffusion method. RESULTS: All hydroxyapatite (HA)/collagen-saturated diluted antibiotics showed elliptical inhibition zones on the corresponding agar plates. For both antibiotics, there was a linear correlation between dilution and area of the inhibition zone. CONCLUSION: The analysis showed that the antimicrobial activity of HA/collagen-saturated antibiotics corresponded to the antimicrobial dilutions. These results should be further analyzed using in vivo studies to determine the remaining antibiotic efficiency after implantation of bone graft substitutes.

Effect of raloxifene on bone mineral density in premenopausal women at increased risk of breast cancer.

CONTEXT: Raloxifene is a promising breast cancer prevention agent in postmenopausal women at increased risk for breast cancer. The effects of raloxifene in premenopausal women are unknown. OBJECTIVE: We evaluated the effect of raloxifene in premenopausal women at increased risk for breast cancer on bone mineral density (BMD). DESIGN: This was a phase II clinical trial. SETTING: This study was conducted at an academic medical center. PARTICIPANTS: Thirty-seven premenopausal women at increased risk for breast cancer enrolled in the trial. Thirty subjects began treatment and 27 were evaluable. INTERVENTION: Raloxifene (60 mg daily) and elemental calcium (500 mg daily) were given for 2 yr. Subjects were followed up off medications for 1 yr. MAIN OUTCOME MEASURE: The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry. RESULTS: The mean baseline lumbar spine density was 1.027 g/cm(2). Lumbar spine density decreased 2.3% at 1 yr (P < 0.00001) and 3.5% at 2 yr (P < .00001). Percent change from yr 2 to 3 was +1.4%. The mean baseline total hip bone density was 0.905 g/cm(2). Total hip density decreased 0.3% at 1 yr and 1.0% at 2 yr (P = 0.033). Percent change from yr 2 to 3 was +1.7%. CONCLUSIONS: Raloxifene use is associated with a decrease in BMD in premenopausal women at increased risk for breast cancer. The clinical significance of this decrease is unknown and is attenuated with stopping raloxifene.

Programmed instruction: biotherapy, module IV. interleukins.

This is the fourth in a series of five self-learning modules reviewing biotherapy. The focus of this module is the interleukins, biological response modifiers utilized in the treatment of some cancers.