Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning.

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients.

D1/5 dopamine receptors are necessary for learning a novel context.

Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual learning. Here we show that intraperitoneal injection of the dopamine D1/5R antagonist SCH23390 impairs contextual fear conditioning and tone-shock association, while intrahippocampal injection only impairs contextual fear conditioning. By using the context pre-exposure facilitation effect test, we show that SCH23390 is able to block the encoding of the context during the pre-exposure phase. Thus, we provide additional evidence that dopamine is involved in encoding conjunctive representations of new contexts.

Localized Chronic Form of Langerhans Cell Histiocytosis in the Femur of a 16-Year-Old Male Successfully Treated with Radiofrequency Ablation.

Only three cases of patients suffering from a localized chronic form of Langerhans cell histiocytosis (LCH) successfully treated with radiofrequency ablation (RFA) have been published so far. This is the first case report of a patient with a localized chronic form of LCH of the femur, which was successfully treated with percutaneous image-guided RFA, and who was evaluated pre-RFA and followed up post-RFA for a period of 48 months, in order to validate the safety and efficacy of this method and to obtain imaging studies depicting the actual in situ changes taking place post-RFA. RFA was proved to be a safe and efficient method when treating patients with a localized chronic form of LCH.

Direct superior approach with standard instrumentation for total hip arthroplasty: safety and efficacy in a prospective 200-case series.

INTRODUCTION: Direct Superior Approach (DSA) is a muscle sparing approach for total hip arthroplasty (THA) implemented using special instrumentation. There is a lack of information in the literature concerning DSA with standard instrumentation. MATERIALS AND METHODS: 238 patients were recruited for primary THA by a single surgeon from January 2016 until May 2017. 209 patients underwent THA through DSA approach with non-offset acetabular reamers and femoral broaches. We evaluated accuracy of implantation, complications and early functional results. Independent orthopaedic surgeons performed the clinical and radiographic assessments. RESULTS: 200 patients were followed for a year. 3 different implants were used. No sciatic nerve palsies, hip dislocations or fractures were recorded. There was one acute deep and superficial wound infection. The mean functional score was significantly improved at all follow-ups (p < 0.001). 97% of stems were inserted into the neutral coronal and 96% in neutral sagittal alignment. All cups fell within a safe zone of inclination and 91% of anteversion. 2 hips demonstrated heterotopic ossification, Brooker class I. Obese patients had no increased risk of complications. CONCLUSIONS: DSA with standard instrumentation is safe and efficacious for THA. It offers fast recovery and facilitates correct implantation of different implants, can be useful even for hip dysplasia and obese patients with minimal complication rates.

Serum levels of Dkk-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters.

OBJECTIVE: To evaluate serum Dickkopf-1 (Dkk-1), sclerostin and vascular endothelial growth factor (VEGF) levels in patients with ankylosing spondylitis (AS) compared to healthy controls as well as their association with smoking, and clinical, inflammatory and radiographic parameters. METHODS: Serum samples for total Dkk-1, sclerostin and VEGF were obtained from 57 tumour necrosis factor (TNF) inhibitor naïve patients with AS and 34 sex-, age- and body mass index (BMI)-matched controls. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), modified Stroke AS Spine Score (mSASSS) and smoking status were assessed for each patient. RESULTS: There was no significant difference in serum bone metabolism markers between AS patients and controls. Dkk-1 levels were significantly (P<0.05) higher in AS patients with elevated ESR and CRP and no syndesmophytes, and were significantly (P<0.001) correlated with sclerostin levels (r=0.592). VEGF levels were significantly (P<0.05) higher in AS patients with current and ever smoking, elevated ESR and CRP, and high BASDAI and BASFI, and were significantly (P<0.05) correlated with ESR (r=0.284), CRP (r=0.285), BASDAI (r=0.349) and BASFI (r=0.275). In multivariate regression analyses, high Dkk-1 levels were significantly (P≤0.001) associated with elevated ESR and CRP, no syndesmophytes and high sclerostin levels, and high VEGF levels significantly (P<0.05) with ever smoking, and elevated ESR and CRP. CONCLUSION: In AS, serum Dkk-1 concentrations appear to be related not only to syndesmophyte formation but also to systemic inflammation. Furthermore, high VEGF levels may be associated with smoking exposure.

Curve progression 25 years after bracing for adolescent idiopathic scoliosis: long term comparative results between two matched groups of 18 versus 23 hours daily bracing.

BACKGROUND: Scoliotic curves do not necessarily stop progressing at skeletal maturity. The factors that influence curve behavior following bracing are not fully determined. Our objectives were to evaluate the loss of the scoliotic curve correction in a cohort of patients treated with bracing during adolescence and to compare the outcomes of 18 versus 23 h of bracing at a mean of 25 years post brace removal. METHODS: Seventy-seven patients, who were successfully treated for Adolescent Idiopathic Scoliosis with Βoston brace, were re-evaluated 25 years after the end of their treatment. Patients were further divided in 2 matched groups; those wearing the brace for 23 h and those not wearing the brace at school-time, limiting the application of the brace to 18 h. The mean scoliotic curve was compared between groups before, during, just after bracing and 25 years post bracing. Validated in patients' native language forms of Short Form 36 and Oswestry Disability Index questionnaires were used to compare the quality of life between groups 25 years post bracing. RESULTS: The mean age of the cohort was 40.4 (±3.2) years. They underwent long term follow up at a mean of 25.16 (±2.69) years after brace removal. The mean cohort scoliotic curve increased by 3.9 (±6.69) at 25 years since brace removal. There was however no significant difference in the mean Cobb angle of the cohort between pre brace and long term follow up period (p = 0.307). The 18 and 23 h application groups were comparable according to demographics and several bracing and scoliotic curve parameters. There was no significant difference in the mean curve magnitude between 18 and 23 h application groups at brace removal (p = 0.512) and at 25 years follow-up (p = 0.878). There was also no significant difference in the mean score of Quality of Life questionnaires between groups at long term follow up. CONCLUSION: Scoliotic curves do not necessarily stop progressing after bracing. Bracing is effective treatment method with good long term results in appropriate patients. Since compliance was not objectively measured, we don't feel confident to give any indication about everyday dosage.

The effect of smoking on clinical and radiographic variables, and acute phase reactants in patients with ankylosing spondylitis.

To investigate the association between smoking and clinical, inflammatory and radiographic parameters in patients with ankylosing spondylitis (AS). One hundred and six tumour necrosis factor inhibitor naïve patients with AS were included in the study. The erythrocyte sedimentation rate, C-reactive protein, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI) and modified Stroke AS Spine Score (mSASSS) were assessed cross-sectionally for each patient. Smoking history was obtained, and smoking pack years were calculated. Current smokers had significantly higher BASDAI (p < 0.001) and a trend for higher BASFI (p = 0.059). Ever smokers had significantly higher BASFI (p = 0.035) and a trend for higher mSASSS (p = 0.063) compared to never smokers. Pack years (smoking intensity) were positively correlated with duration of inflammatory back pain (r = 0.628, p < 0.001), BASFI (r = 0.443, p < 0.001) and mSASSS (r = 0.683, p < 0.001). Multivariate regression analyses showed that current smoking was independently associated with a higher BASDAI score [regression coefficient (B) = 14.75, p < 0.001] and increasing pack years were independently associated with higher mSASSS (B = 0.26, p = 0.005). In patients with AS, current smoking was strongly and independently associated with higher disease activity, and cumulative smoking exposure with more radiographic spinal damage. In AS smokers, smoking cessation should be strongly recommended.

Management of glucocorticoid-induced osteoporosis: clinical data in relation to disease demographics, bone mineral density and fracture risk.

INTRODUCTION: Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis. Patient selection and the treatment choice remain to be controversial. None of the proposed management guidelines are widely accepted. We evaluate the available clinical data, the efficacy of current medication and we propose an overall algorithm for managing GIOP. AREAS COVERED: This article provides a critical review of in vivo and clinical evidence regarding GIOP and developing evidence-based algorithm of treatment. Data base used includes MEDLINE® (1950 to May 2014). EXPERT OPINION: Patient-specific treatment is the gold standard of care. Glucocorticoid (GC)-treated patients must comply with a healthy lifestyle and receive 1000 mg of calcium and at least 800 mg of Vitamin D daily. Bisphosphonate (BP) therapy is the current standard of care for prevention and treatment of GIOP. Most of bisphosphonates demonstrated benefit in lumbar bone mineral density (BMD) and some in hip BMD. Alendronate, risedronate and zoledronate showed vertebral anti-fracture efficacy in postmenopausal women and men. Scarce data however when compared head to head with BP efficacy. In post-menopausal women, early antiresorptive BP treatment appears to be efficient and safe. In premenopausal women and patients at high risk of fracture receiving long-term GC therapy however, teriparitide may be advised alternatively.

Circulating periostin levels in patients with AS: association with clinical and radiographic variables, inflammatory markers and molecules involved in bone formation.

OBJECTIVE: The aim of this study was to evaluate serum periostin levels in patients with AS in comparison with healthy controls as well as their association with clinical, inflammatory and radiographic parameters and molecules involved in bone formation. METHODS: Serum samples for periostin, total Dickkopf-1 (Dkk-1), sclerostin, VEGF and inflammatory markers were obtained from 65 TNF inhibitor-naive patients with AS. The BASDAI, BASFI, modified Stoke AS Spine Score and BASRI for the spine (BASRI-s) were assessed for each patient. Serum periostin levels were also measured in 36 sex-, age- and BMI-matched controls. RESULTS: Serum periostin levels were significantly lower in AS patients compared with controls [234.4 pg/ml (s.e.m. 7.5) vs 291.4 (s.e.m. 8.3), respectively; P < 0.001]. Periostin levels were higher in AS patients with elevated CRP (P = 0.005), high BASDAI (P = 0.014) and low BASRI-s (P = 0.033) and were correlated with BMI (r = -0.304, P = 0.014), ESR (r = 0.395, P = 0.001), CRP (r = 0.413, P = 0.001), BASRI-s (r = -0.242, P = 0.047) and sclerostin (r = -0.280, P = 0.024). In multiple regression analysis, periostin levels were an independent variable of CRP (ß = 0.160, P = 0.009) and sclerostin levels (ß = -0.311, P = 0.012). CONCLUSION: Our data suggest that periostin levels are low in patients with AS. Among AS patients, periostin levels are higher in those with higher disease activity, higher systemic inflammation and less extensive radiographic damage. Periostin is independently associated with CRP and sclerostin levels.

Measured resection versus gap balancing technique for femoral rotational alignment: a prospective study.

PURPOSE: To compare the measured resection technique and the gap balancing technique for correction of the femoral rotational alignment. METHODS: 57 women and 6 men (mean age, 70 years) with end-stage osteoarthritis and <15º malalignment and <10º flexion contracture of the knee underwent primary total knee arthroplasty through the medial approach using the measured resection technique (n=34) or the gap balancing technique (n=29). Femoral rotational alignment was evaluated before and 7 days after surgery using computed tomography by referencing the 2 posterior condyles to the transepicondylar axis. RESULTS: The 2 groups did not differ significantly in terms of correction of the femoral rotational alignment (3.4º ± 1.4º vs. 3.5º ± 3.1º, p=0.817). CONCLUSION: The measured resection and the gap balancing techniques achieved comparable correction of femoral rotational alignment.

Leflunomide addition in patients with articular manifestations of psoriatic arthritis resistant to methotrexate.

In contrast to rheumatoid arthritis, in psoriatic arthritis (PsA), the efficacy of disease-modifying antirheumatic drugs (DMARDs) combination has not been documented. We conducted a retrospective study to evaluate the effectiveness of leflunomide (LEF) addition in 11 PsA patients with articular manifestations that failed to respond to methotrexate (MTX) monotherapy [disease activity score in 28 joints (DAS28) > 3.2)]. Eight of them, all with moderate disease activity (DAS28 < 5.1) at baseline, tolerated the combination. A statistically significant improvement of the mean DAS28, based on erythrocyte sedimentation rate (ESR), and its variables, and C-reactive protein (CRP) at 12-16 weeks after LEF addition was observed. Mean change of DAS28 in patients with polyarticular disease did not differ compared with those with oligoarticular. Based on the European League Against Rheumatism (EULAR) response criteria, none of our patients achieved a good response, seven had a moderate response, and one was a non-responder. The two patients with the lower DAS28 at baseline attained low disease activity (LDA, DAS28 ≤ 3.2), while none reached remission (DAS28 ≤ 2.6). Achievement of clinical remission or at least LDA has been recently proposed as the goal of treatment in PsA. Our results imply that LEF addition may serve as an alternative therapeutic modality for patients with moderately active PsA and, as lower as possible, residual disease activity after the initial therapy with MTX alone.

Serum intact-parathyroid hormone level following total knee arthroplasty.

PURPOSE: To evaluate short-term parathyroid hormone (PTH) secretion following total knee arthroplasty (TKA). METHODS: 119 Caucasian postmenopausal women aged 49 to 81 (mean, 69.8) years who underwent TKA for end-stage knee osteoarthritis were included. Serum levels of intact-PTH, calcium, phosphorus, and creatinine were evaluated pre- and post-operatively (on days -1 and 7). Creatinine clearance was also calculated. RESULTS: In 67 of the patients, serum intact-PTH levels decreased after TKA; this sample proportion was not significant (p=0.82). In 16 of the patients, such levels elevated abnormally (above normal range). In the remaining 36 patients, such levels elevated within the normal range. Therefore, the mean serum intact- PTH level of all patients increased slightly after TKA (45.4 vs. 45.3, p=0.162). The serum intact-PTH level did not correlate to body weight (r=-0.045, p=0.624), patient age (r=-0.061, p=0.508), serum creatinine level (r=0.084, p=0.366), and clearance of creatinine (r=-0.037, p=0.692). CONCLUSION: In most postmenopausal women, the serum intact-PTH level decreased moderately following TKA, but in some, the level was abnormally elevated. This may interfere the prosthesis incorporation process.

Radial head replacement with the MoPyC pyrocarbon prosthesis.

BACKGROUND: Radial head fractures often pose therapeutic dilemmas. We present the early results of patients who underwent radial head replacement with the MoPyC prosthesis (Bioprofile, Tornier, Saint-Ismier, France). MATERIALS AND METHODS: We re-evaluated patients who underwent post-traumatic radial head resection and implantation of the MoPyC prosthesis due to pain and motion restriction. All patients underwent radiographic evaluation. Clinical evaluation was performed using the Broberg-Morrey and the Mayo Elbow Performance Score (MEPS) scales. RESULTS: Thirty-two patients (20 men, 12 women; mean age, 54 years; 22 dominant upper limbs) were evaluated. Twenty had a comminuted radial head fracture (Mason IV, 15; Mason III, 5), 2 from radial head fracture malunion, and 10 had complex elbow injuries (comminuted radial head fractures with ligamentous ruptures with or without coronoid process fractures). Mean follow-up was 27 months (range, 21-46 months). The mean results at the latest follow-up were flexion-extension, 130° (range, 105°-150°); pronation, 74° (range, 60°-80°); and supination, 72° (range, 60°-80°). No laxity was evident during valgus and varus stress tests. Mean grip strength was 96% of the contralateral side. Broberg-Morrey scores were excellent in 33%, good in 44%, and fair in 23%. MEPS results were excellent in 80%, good in 17%, and fair in 3%. There were 6 cases of periprosthetic lucencies or osteolysis of the radius without any clinical signs of loosening. CONCLUSIONS: Radial head replacement with the MoPyC pyrocarbon prosthesis (when performed in carefully selected patients) yields satisfactory results regarding range of motion and function of the elbow joint.

Efficacy of leflunomide addition in relation to prognostic factors for patients with active early rheumatoid arthritis failing to methotrexate in daily practice.

The recommendations of the European League Against Rheumatism (EULAR) for the management of rheumatoid arthritis (RA) suggest a different therapeutic approach to methotrexate (MTX) resistance according to the presence or absence of poor prognostic factors. Retrospectively, in our patients with active early RA (disease activity score in 28 joints (DAS28) > 3.2) that failed to respond to initial MTX monotherapy, we investigated whether leflunomide (LEF) addition had a different efficacy when associated with the presence or absence of poor prognostic factors. Of the 20 patients who received LEF, 15 (2 males and 13 females) tolerated the combination. Five patients had no poor prognostic factors, and 4 (80%) of those patients achieved remission or low disease activity (LDA) according to DAS28 and also a good response with the EULAR criteria. Of the 10 patients with at least one poor prognostic factor, remission or LDA occurred in 4 (40%) of the patients, and a good EULAR response was obtained in 3 (30%) of the patients. By Fisher's exact test, no significant difference was found between the two groups of patients in remission or LDA (p = 0.28) according to DAS28 and a good response (p = 0.12) with the EULAR criteria. In all patients with an inadequate response to the LEF+MTX combination, the substitution of a TNF inhibitor for LEF or the addition of a TNF inhibitor to the combination led to remission or LDA. Large studies are required to investigate the efficacy of LEF addition in relation to prognostic factors in patients with active early RA that did not respond to the initial therapy with MTX alone.

Reduction of Acute Anterior Dislocation with the FARES Method.

INTRODUCTION: The FARES (Fast, Reliable, and Safe) method is a new way to reduce acute anterior glenohumeral dislocations that combines the application of gentle longitudinal traction, vertical oscillation movements, and abduction and external rotation of the arm. STEP 1 POSITION THE PATIENT: Place the patient supine on a stretcher, with his/her elbow extended, and advise him/her to hold the stretcher with the opposite hand. STEP 2 BRIEF THE PATIENT: Convince the patient that his/her cooperation is necessary for a better outcome. STEP 3 HOLD THE ARM: Holding the patient's hand with both of your hands, with his/her elbow extended and forearm in neutral rotation, start the procedure at 30° of shoulder abduction. STEP 4 APPLY TRACTION AND ADD OSCILLATIONS: Applying gentle longitudinal traction to keep the arm extended, add gentle vertical oscillating movements. STEP 5 ABDUCT AND EXTERNALLY ROTATE THE ARM: Gradually abduct the arm to 90° and then gradually externally rotate the arm to achieve full external rotation. STEP 6 ACHIEVE REDUCTION: The dislocation is usually reduced once 120° to 150° of shoulder abduction has been achieved. RESULTS: In our previously published prospective randomized study, the FARES method was compared with the Hippocratic and the Kocher methods12. WHAT TO WATCH FOR: IndicationsContraindicationsPitfalls & Challenges.

The serum levels of Receptor Activator of Nuclear Factor-κB Ligand, bone-specific alkaline phosphatase, osteocalcin and osteoprotegerin do not correlate with the radiographically assessed severity of idiopathic hip and knee osteoarthritis.

OBJECTIVES: Determination of the serum levels of Receptor Activator of Nuclear Factor-Κb Ligand, bone-specific alkaline phosphatase, osteocalcin and osteoprotegerin in patients suffering from osteoarthritis of varying severity and healthy controls and correlation of these results with the patients' age and the radiographically assessed severity of the disease. DESIGN AND METHODS: Patients suffering from hip (n=58) or knee (n=117) osteoarthritis and matched controls (n=19) were enrolled in this study. Patients underwent physical examination and standard radiographic evaluation before blood sampling. RESULTS: The serum levels of osteoprotegerin were positively correlated with age in all groups, whereas those of osteocalcin in the 'knee' group only. Osteoarthritis' severity and location did not have a statistically significant impact on the mean serum level of any marker in both groups. CONCLUSIONS: Based on our results, none of the studied markers can serve as a surrogate for radiographic imaging in patients suffering from hip and knee osteoarthritis.

Participation in athletic activities may be associated with later development of hip and knee osteoarthritis.

Participation in physical activity and recreational sports is critical for maintaining overall health; athletic activities and reduction in the incidence of several "lifestyle" diseases seem to have a dose-dependent relationship. Also, quality of life is enhanced in people who are active and regularly participate in sports. However, sports-related joint loading and strenuous occupational loading have been shown to increase the risk of osteoarthritis (OA), which seems to have a multifactorial etiology. This article reviews the literature on known connections between participation in sports and athletic activities and development of secondary OA in the joints of the major upper and lower limbs (ie, knee, hip, elbow, and shoulder) in athletes without injury. Most studies examining the connection between participation in sports and later development of OA usually provide low-level evidence and have many methodological weaknesses. Based on the literature reviewed in this article, it may be concluded that the connection between participation in athletic activities and development of OA has not been proven; however, the condition is highly likely to occur in the hip and knee joints. Definite conclusions regarding the connection between development of glenohumeral and/or elbow OA and participation in athletic activities cannot be drawn.