Naltrexone modulates contextual processing in depression.

Context, the information surrounding an experience, can significantly alter the meaning and the affective responses to events. Yet the biological mechanisms through which context modulate experiences are not entirely understood. Here, we hypothesized that the µ-opioid system-extensively implicated in placebo effects, a clinical phenomenon thought to rely on contextual processing-modulates the effects of contextual information on emotional attributions in patients with depression. To test this hypothesis, 20 unmedicated patients with depression completed a randomized, double-blind, placebo-controlled, crossover study of one dose of 50 mg of naltrexone, or placebo immediately before completing two sessions of the Contextual Framing fMRI task. This task captures effects of valenced contextual cues (pleasant vs. unpleasant) on emotional attribution (the rating of subtle emotional faces: fearful, neutral, or happy). Behaviorally, we found that emotional attribution was significantly moderated by the interaction between contextual cues and subtle emotional faces, such that participants' ratings of valenced faces (fearful and happy), compared to neutral, were more negative during unpleasant, compared to pleasant context cues. At a neural level, context-induced blood-oxygen-level-dependent responses in the ventromedial prefrontal cortex, the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the lateral orbitofrontal cortex, significantly moderated the effects of context on emotional attribution, and were blunted by naltrexone. Furthermore, the effects of naltrexone on emotional attribution were partially abolished in more severely depressed patients. Our results provide insights into the molecular alterations underlying context representation in patients with depression, providing pivotal early data for future treatment studies.

Prefrontal expectancy and reinforcement-driven antidepressant placebo effects.

Placebo responses in depression exemplify how expectancies and appraisals impact mood. Cognitive and neural mechanisms underlying these responses are still poorly understood, partly due to the difficulty of simulating antidepressant effects and manipulating mood experimentally. To address these challenges, we developed an acute antidepressant placebo experiment involving the intravenous administration of a "fast-acting antidepressant" and a trial-by-trial sham fMRI "neurofeedback" manipulation, purporting to reveal mood-relevant neural responses. Twenty volunteers with major depression underwent this experiment while rating their expected and actual mood improvement. Mixed-effects analyses of trial-by-trial ratings revealed that the "drug" infusion cues induced higher expectancies of mood improvement, while both the "drug" infusion cue and the sham neurofeedback induced a reported mood improvement. Neurofeedback of greater magnitude, compared to lower magnitude, recruited the lateral prefrontal cortex (lPFC). Individuals with greater lPFC responses to neurofeedback displayed: (1) greater effect of previous mood improvement on expectancy ratings and (2) greater effect of sham neurofeedback on mood improvement. Behavioral antidepressant placebo effects were additionally moderated by changes in peripheral ß-endorphin plasma levels and depressive symptomatology. These data demonstrate the feasibility of trial-by-trial manipulation of antidepressant placebo-associated expectancies and their reinforcement. We provide initial insights into the role of the lPFC in the interplay between placebo-induced expectancies and mood, as well as preliminary evidence for the role of the opioid system in antidepressant placebo effects.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Molecular mechanisms of placebo responses in humans.

Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective µ-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.

FAAH selectively influences placebo effects.

Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms. To further understand the human implications of the interaction between these two systems, we investigated the role of the common, functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, on psychophysical and neurotransmitter (dopaminergic, opioid) responses to pain and placebo-induced analgesia in humans. FAAH Pro129/Pro129 homozygotes, who constitute nearly half of the population, reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration; no effects on pain report in the absence of placebo were observed. Pro129/Pro129 homozygotes also showed greater placebo-induced µ-opioid, but not D(2/3) dopaminergic, enhancements in neurotransmission in regions known involved in placebo effects. These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects.

Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits.

BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.

Anterior versus posterior approach in 3D correction of adolescent idiopathic thoracic scoliosis: a meta-analysis.

PURPOSE: Systematic review was conducted to compare effectiveness and safety of anterior and posterior surgical approach in 3D correction of adolescent idiopathic thoracic scoliosis. METHODS: Data sources were MEDLINE and SCOPUS databases. We included studies on the use of either anterior or posterior instrumentation, or their combination, in surgical correction of adolescent idiopathic thoracic scoliosis, with at least 10 enrolled patients, aged less than 20 years at the time of surgery, and a follow-up of at least 24 months. A study was eligible if it reported the number of patients, mean estimate and dispersion of three key outcome measures (frontal and sagittal Cobb angle, apical vertebra rotation according to Perdriolle) at three measurement points (preoperatively, postoperatively, at follow-up). The quality of studies was assessed using the scale by Pilkington. RESULTS: Although 24 articles met the inclusion criteria, no randomized controlled trials (RCT) was identified. None of the articles was of high quality. Both instrumentations provided a similar degree of reduction of frontal Cobb angle. Long-term effects of surgical correction on the sagittal Cobb angle seemed to be more stable in patients treated by posterior approach, while the anterior approach was more effective in the reduction of apical vertebral rotation. The surgery parameters were more favorable for anterior approach, particularly for the number of fused vertebrae. CONCLUSIONS: Although the available evidence favors neither of the two approaches, our study revealed several important issues: the reports are heterogeneous and provide incomplete relevant information. High quality studies, particularly RCT, are called for. LEVEL OF EVIDENCE: Level II.

Patellar tendinopathy: histopathological examination and follow-up of surgical treatment.

PURPOSE OF THE STUDY: The aim of this study was to determine the exact localization of the histopathological process (bone, bone-tendon junction or tendon), and to determine whether the underlying pathologic process is predominantly of inflammatory or degenerative nature, then to evaluate the outcome of the surgical treatment of patellar tendinopathy. MATERIALS: A prospective cohort study was performed in order to analyze the outcome of surgical treatment of patellar tendinopathy, as well as to document histopathological changes in bone, bone-tendon junction, and in the patellar ligament in 34 professional athletes treated with patellar apicotomy. All the patients included in the study were classified as stage 3 according to Blazina and showed no improvement after at least 6 months of conservative treatment. The postoperative follow-up was from 1 to 8 years with a mean value of 4.7 years. METHODS: The postoperative results were analyzed using a semiquantitative scoring system where the functional outcome was classified as very good if the athlete returned to his sporting activity without any negative side effects, good if the athlete resumed his sporting activities with modest painful sensations present only at the maximum level of physical exertion, and poor if any reduction of athletic activity was present. In twenty patients a histopathological examination of resected bone and tendon tissue was performed. The specimens were stained with hematoxylin-eosin and examined under a light microscope using polarization. Special stains used were Alcian blue, to detect any increase in ground substance, and Prussian blue which enhances conspicuity of hyaline degeneration and enables detection of hemosiderin. Immunohistochemistry was performed in order to analyze presence of blood vessels, leukocytes and histiocytes. RESULTS: Very good results were achieved in 20 of operated knees, good results were achieved in 12 of knees and poor results were achieved in 2 of operated knees. Pathological changes in the bone were found in 35% of analyzed specimens, abnormality at the bone-tendon junction were found in 75% of the specimens, and changes in the patellar tendon were found in all extracted specimens. The histopatholological nature of the lesions found within the tendon tissue in all of the analyzed specimens belongs to the group of degenerative changes. DISCUSSION: Currently a consenus has been established that the expression tendinitis is "out", and the term tendinopathy should be used instead. No inflammatory cells and no increase in prostaglandins can be detected in the tendons. Histopathological studies of the tissue fibrils affected by tendinosis characteristically demonstrate hypercellularity, hypervascularity, lack of inflammatory infiltrates, and disorganization and loosening of collagen fibers. CONCLUSION: The clinical results and histopathological examination in our series justified our operative method. In the chronic stage these lesions are irreversible and constitute permanent intratendinous lesions. It thus seems logical to excise these lesions from their origin at the apex of the patella and entry into the adjacent tendon. It is also recommended on the basis of our and other authors' research that the term patellar tendinopathy should be used instead of tendonitis/tendinitis.

Articular cartilage repair by genetically modified bone marrow aspirate in sheep.

Bone marrow presents an attractive option for the treatment of articular cartilage defects as it is readily accessible, it contains mesenchymal progenitor cells that can undergo chondrogenic differentiation and, once coagulated, it provides a natural scaffold that contains the cells within the defect. This study was performed to test whether an abbreviated ex vivo protocol using vector-laden, coagulated bone marrow aspirates for gene delivery to cartilage defects may be feasible for clinical application. Ovine autologous bone marrow was transduced with adenoviral vectors containing cDNA for green fluorescent protein or transforming growth factor (TGF)-beta1. The marrow was allowed to clot forming a gene plug and implanted into partial-thickness defects created on the medial condyle. At 6 months, the quality of articular cartilage repair was evaluated using histological, biochemical and biomechanical parameters. Assessment of repair showed that the groups treated with constructs transplantation contained more cartilage-like tissue than untreated controls. Improved cartilage repair was observed in groups treated with unmodified bone marrow plugs and Ad.TGF-beta1-transduced plugs, but the repaired tissue from TGF-treated defects showed significantly higher amounts of collagen II (P<0.001). The results confirmed that the proposed method is fairly straightforward technique for application in clinical settings. Genetically modified bone marrow clots are sufficient to facilitate articular cartilage repair of partial-thickness defects in vivo. Further studies should focus on selection of transgene combinations that promote more natural healing.

Double synovial cyst of the proximal tibiofibular joint confirmed by MRI as a cause of the peroneal tunnel syndrome.

The aim of this case report is to present an unusual double synovial cyst that arose from the proximal tibiofibular joint compressing the peroneal nerve in the peroneal tunnel and was unrecognized at the beginning. According to the review of literature back to 1891, only 62 cases of cysts originating from the proximal tibiofibular joint (PTFJ) have been described. We report a case of a 32 year old male patient who was admitted to the Department of Orthopaedic Surgery because of a classic peroneal tunnel syndrome of the left leg. On the lateral side of the proximal third of his left leg a tumefaction of 12 x 2.5 cm was visible. The sonography showed a characteristic image of the para-articular synovial cyst of the left knee. A surgical extirpation of the synovial cyst and decompression of the peroneal nerve in the peroneal tunnel were performed. PHD confirmed a classic synovial cyst. Postoperatively, the symptoms of the peroneal nerve compression disappeared. Three years after the first surgical intervention the patient was readmitted to the Department because of quite similar problems, only the neurological symptoms were less intensive than during the first admittance. This time the performed MR imaging showed a double synovial cyst originating from the proximal tibiofibular joint. The surgical treatment consisted of a total extirpation of both cysts including the narrow stalks of communication with the PTFJ. The joint was opened and a synovectomy was done using an electrocauter and a sharp curette. Regular check-ups were done every 6 months and twice during the control period of 4 years, as was the MR imaging control. MRI findings 4 years after the second surgical intervention were normal. Clinical findings after 7 years were normal and we are sure that the recidivation of the synovial cyst excluded. The MRI diagnostics was crucial for an adequate surgical treatment and the relief of the peroneal tunnel syndrome symptoms.

Injuries in synchronized skating.

Synchronized skating is a relatively new competitive sport and data about injuries in this discipline are lacking. Therefore the purpose of this study was to investigate the frequency and pattern of acute and overuse injuries in synchronized skaters. Before and during the World Synchronized Skating Championship 2004, a questionnaire inquiring about the frequency of injuries in this skating discipline was given to 23 participating teams. A total of 514 women and 14 men senior skaters completed the questionnaires (100 % response). Two hundred and eighteen (42.4 %) female and 6 (42.9 %) male skaters had suffered from acute injuries during their synchronized skating career. As some skaters had suffered from more than one injury, the total number of acute injuries in females was 398 and in males 14. In female skaters 19.8 % of acute injuries were head injuries, 7.1 % trunk, 33.2 % upper, and 39.9 % lower extremity injuries. In male skaters 14.3 % were head injuries, 28.6 % upper, and 57.1 % lower extremity injuries, with no report of trunk injuries. Sixty-nine female and 2 male skaters had low back problems and 112 female and 2 male skaters had one or more overuse syndromes during their skating career. Of 155 overuse injuries in female skaters, 102 (65.8 %) occurred during their figure skating career, while 53 injuries (34.2 %) only occurred when they skated in synchronized skating teams. In male skaters, out of 5 overuse injuries, 4 (80 %) occurred in their figure skating career, while 1 (20 %) occurred during their synchronized skating career. Out of the total of 412 injuries, 338 (82 %) occurred during on-ice practice, while 74 (18 %) happened during off-ice training. Ninety-one (26.9 %) acute injures occurred while practicing individual elements, and 247 (73.1 %) on-ice injuries occurred while practicing different team elements. We conclude that injuries in synchronized skating should be of medical concern due to an increasing number of acute injuries, especially those that go beyond the soft tissue and include head injuries and fractures. We feel that these more significant injuries MAY TO SOME EXTENT BE attributable to the increasing physical demands and technical difficulty required of the teams now participating in a more competitive environment over the last four years.

Current concepts in gene therapy of the musculoskeletal system.

The purpose of this article is to review the remarkable progress in the field of musculoskeletal system gene therapy. Since the introduction of this concept 15 years much of the preclinical and clinical data have emerged. The original target, rheumatoid arthritis, has been subjected to clinical phase II efficacy protocol, and osteoarthritis gene therapy efficacy is being thoroughly investigated in various animal models. The most promising area of research in this field however, is the tissue repair, because it doesn't require prolonged period of gene expression, local delivery is reasonably simple and it avoids substantial risk associated with systemic delivery, and levels of gene expression don't need to be so finely regulated. Gene transfer is successfully being used to aid the repair and regeneration of bone, cartilage, ligament tendon, meniscus and intervertebral disc. Other potential applications of gene therapy in musculoskeletal system include osteoporosis, aseptic loosening, genetic diseases and tumors. Highly encouraging data gained from these studies have confirmed that gene therapy is a promising therapeutic solution to treat various musculoskeletal system disorders.

Stress fractures of the femoral shaft in athletes: a new treatment algorithm.

BACKGROUND: Femoral shaft stress fractures in athletes are not common but pose a great diagnostic challenge to clinicians. Because of few clinical signs, diagnosis and treatment are often delayed. Furthermore, if not treated correctly, these fractures are well known for complications and difficulties. OBJECTIVE: To develop a well structured and reproducible treatment algorithm for athletes with femoral shaft stress fractures. METHODS: The proposed algorithm is carried out in four phases, each lasting three weeks, and the move to the next phase is based on the result of the tests carried out at the end of the previous phase. Over nine years, we treated seven top level athletes, aged 17-21. In all athletes, diagnosis was based on physical examination, plain radiographs, and bone scan. RESULTS: As a result of the treatment method, all the athletes were fully engaged in athletic activity 12-18 weeks after the beginning of treatment. After completion of the treatment, the athletes were followed up for 48-96 months. During the follow up, there was no recurrence of discomfort or pain, and all the athletes eventually returned to competition level. CONCLUSION: These results and data available from the literature suggest that the algorithm is the optimal treatment protocol for femoral shaft stress fractures in athletes, avoiding the common complications and difficulties.

Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis.

We randomly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups: (1) autologous iliac graft (n=6), (2) autologous iliac graft + osteogenic protein-1 (OP-1; n=6), and (3) allogenic iliac graft + OP-1 (n=5). Radiographic, scintigraphic, and clinical assessments were performed throughout the follow-up period of 24 months. OP-1 improved the performance of both autologous and allogenic bone implants and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1. Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone. The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure. Consequently the harvesting of autologous graft can be avoided.

Multiple stress fractures in a young female runner.

The effect of exercise on female's bone metabolism has received much attention in recent years. We report on unusual case of a female runner with low body mass and amenorrhea, who suffered 4 stress fractures. Three of the stress fractures occurred during her sports career, and the fourth occurred 7 years after the cessation of sports activities. It seems that exercise-induced amenorrhea together with food restriction in the young age may cause long-term consequences on bone metabolism.

Arthroplasty in treating knee osteoarthritis and proximal tibia stress fracture.

The authors describe two cases of severely angulated tibial non-unions after proximal tibia stress fractures associated with ipsilateral osteoarthritis treated with modular knee endoprosthesis with a long tibial stem to stabilize non-union fragments. During the procedure, no additional osteosynthesis or bone grafting was added. Both non-unions healed after 6 months with no post-operative complications. The authors suggest implantation of modular knee endoprosthesis, as a single procedure, in treatment of proximal tibia non-union after a stress fracture as a result of severe varus/valgus deformity. It provides a solution for osteoarthritis treatment, axis correction and non-union osteosynthesis.

Compressed homologous cancellous bone and bone morphogenetic protein (BMP)-7 or bone marrow accelerate healing of long-bone critical defects.

We studied 18 adult male New Zealand rabbits with a critical right-sided ulnar defect of 15 mm. In six animals the defect was grafted with homologous compressed cancellous bone, in six animals with homologous compressed cancellous bone including 300 micro g bone morphogenetic protein (BMP)-7 and in six animals with homologous compressed cancellous bone including 0.5 ml autologous bone marrow. The defect was studied using radiographs every second week for 10 weeks. At the conclusion of the experiment the animals were killed and the defect studied by histology and histomorphometry. In all animals treated with the addition of autologous bone marrow and in five of six animals treated with the addition of BMP-7, the defect healed. There was no union in animals treated with homologous compressed cancellous bone without additive. The histological picture of the regenerated area was similar in the two experimental groups. Woven bone contained small marrow spaces with fibrous tissue and capillaries. The osteoid seams were on average greater in animals that received autologous bone marrow as compared to animals that received BMP-7.