Ultrasonic Evaluation of the Achilles Tendon in Patients Treated for Congenital Clubfoot: Comparison between Patients Treated with Plaster Alone, Achilles Tenotomy, and Z-Plasty Lengthening.

BACKGROUND: Clubfoot is a common congenital deformity. The Ponseti technique, involving early corrective manipulations followed by applying long leg casts and Achilles tenotomy, is widely accepted as the preferred treatment. Rapid tendon healing after surgery has been documented, but the aspect regarding long-term tendon structure and properties is not known. Three cases of Achilles tendon rupture in adolescents previously treated for clubfoot have been described in the literature. As rupture is a rare event in this age group, a possible correlation with previous surgery has been hypothesized. The primary aim of the study was to compare the ultrasound findings of the Achilles tendon in patients treated for clubfoot, between patients treated with casting alone and with patients who underwent surgery (percutaneous tenotomy or Z-plasty lengthening). METHODS: There were 22 asymptomatic patients (34 feet) with a median age of 12 years, previously treated for clubfoot, that were recruited for this study; the patients underwent an Achilles tendon ultrasound examination during a follow-up outpatient visit. RESULTS: A greater thickness and increased number of structural alterations with the presence of hypoechoic areas of the operated tendons compared with those treated with plaster alone were observed (p-value: 0.0498 and <0.001, respectively). These ultrasound findings were indicative of tendon suffering, as seen in tendinopathies. CONCLUSIONS: The presence of ultrasound alterations in asymptomatic patients operated on for clubfoot requires careful control of the extrinsic factors of tendinopathy in order to reduce the risk of subcutaneous rupture.

The effect of psychosocial interventions on depression, anxiety, and quality of life in hemodialysis patients: a systematic review and a meta-analysis.

PURPOSE: Hemodialysis has become a standard therapy for adults with end-stage renal diseases. Adults undergoing hemodialysis have to cope with unique psychological issues that make their care journey particularly fatiguing. In this systematic review and meta-analysis, we aimed to summarize and evaluate the effects of psychosocial interventions on the reduction of anxiety and depression in adults with HDs. METHODS: We included randomized controlled trials and quasi-experimental studies that measure change in depression, anxiety, and quality of life. RESULTS: We identify three categories of psychosocial interventions delivered to adults undergoing hemodialysis. Based on our analysis, there was a medium effect of psychosocial intervention on depression (SMD - 0.85, 95%CI - 1.17; - 0.52, I2 = 80%, p < 0.01) and anxiety (SMD - 0.99, 95%CI - 1.65; - 0.33, I2 = 88%, p < 0.01) in adults undergoing hemodialysis. CONCLUSIONS: Psychosocial interventions, such as psychological support or relaxation-based therapy, seems all to reduce depression and anxiety in adults undergoing HD. Preliminary evidence suggests that there may be a benefit of psychosocial interventions on the quality of life for adults undergoing HD.

Achilles tendon surgery in clubfoot: Are long term sequelae predictable?

Congenital Clubfoot (CCF) treatment involves a surgical procedure on the Achilles tendon most of the time, i.e. tenotomy or, in selected cases, Z-plasty lengthening. Many authors have studied the outcomes of Achilles tenotomy, describing complete clinical and ultrasound tendon fibers integrity restoration 3-6 weeks after surgery. Nevertheless, little is known about the mechanical properties of the operated tendon. Recently, cases of subcutaneous rupture of the Achilles tendon have been described in adolescents who practiced sports and who had undergone Achilles tenotomy for congenital clubfoot in childhood. Authors report two cases of atraumatic Achilles tendon injury (subcutaneous rupture and intratendinous ossification) in adult patients who had been treated for congenital clubfoot in childhood. In both cases, no causes determining the injury were identified; in the medical history there was a Z-plasty lengthening of the Achilles tendon, performed within the first year of life, which could be considered a predisposing factor. The usefulness of long-term monitoring of patients treated for CCF with surgical procedures on the Achilles tendon is therefore hypothesized, in order to promptly identify by symptoms, clinical pictures and ultrasound criteria, tendon suffering that may predispose subcutaneous rupture.

Congenital Dislocation of the Patella - Surgical Treatment Rationale and Literature Review.

INTRODUCTION: Congenital dislocation of the patella (CDP) is a rare condition and its treatment is not well defined. In CDP, patella is dislocated on the lateral aspect of the distal femur, laterally from the trochlear groove, it cannot be reduced manually and it is almost always associated with genu valgum, lateral torsion of the proximal tibia, and flexion contracture of the knee. This condition is present at birth, but the clinical findings can be subtle at birth due to the size and character of the structures being examined; early diagnosis is essential, but it may be delayed to late childhood or adulthood. If CDP is not promptly treated, the disability increases during growth, so surgical correction should be planned as soon as the diagnosis is confirmed. CASE REPORT: We report a case of bilateral CDP associated with bilateral proximal radioulnar joint stiffness; the patient at the age of diagnosis was 11 years old and underwent a bilateral delayed surgical procedure; the 4-year follow-up results are satisfactory. Surgical treatment rationale and literature are reviewed. CONCLUSION: Surgical correction for CDP is generally recommended, but there is no agreement in literature on the ideal treatment and in some cases, with mild impairment of the knee function, observation alone has been suggested. The decision about a surgical treatment can be difficult and depends on the degree of disability of the patient.

Induced membrane technique for the treatment of severe acute tibial bone loss: preliminary experience at medium-term follow-up.

PURPOSE: Management of acute open tibial fractures with critical bone defect remains a challenge in trauma surgery. Few and heterogeneous cases have been reported about the treatment with the induced membrane technique. METHODS: We prospectively evaluated three patients treated with the induced membrane technique for acute Gustilo IIIB tibial fractures with critical bone defect. Success treatment was defined by bone union with patient pain free. Clinical and radiological evaluations were performed regularly until healing, then annually and with a minimum follow-up of five years. RESULTS: In all patients but one, a success was recorded, respectively, at four and six months. These two patients were pain free until the final follow-up, and no graft resorption or secondary complications related to the index surgery were observed. The third case was managed successfully with a bone transport technique. CONCLUSION: The induced membrane technique is an alternative good option for the treatment of these severe lesions.

Pseudoarthrosis of second metatarsal fracture.

Metatarsal fractures make up the greatest portion of foot fractures in children. Most of them are treated with closed reduction and non-weightbearing cast immobilization.Usually, these fractures heal uneventfully and delay union and pseudoarthrosis are rare. We report a case of a 10-year-old child with non-union of the second metatarsal following a traumatic fracture, caused by an accident 10 months before, and treated successfully by osteosynthesis with plate and screws. Good clinical outcome was achieved at 2 years follow-up.

Transient femoral nerve palsy in spica cast treatment for developmental dysplasia of the hip.

A 4 months and half female child come to our attention for congenital dislocation of the left hip, previously treated in another hospital with abduction bracing, without satisfactory results. After progressive longitudinal bilateral traction, closed reduction under general anesthesia was performed and a spica cast was applied in the so-called human position. The patients remained in the spica cast for 6 weeks and then the plaster cast was renewed in narcosis for another 6 weeks. Once the second cast has been removed left femoral nerve palsy was detected. Orthopaedic treatment was interrupted and in 3 months the nerve completely recovered, while the hip was still stable. We followed the child regularly since then, she is now five years old, she is totally asymptomatic, X-rays shows a residual acetabular dysplasia, with no sign of avascular necrosis.

Revision of 120 tibial infected non-unions with bone and soft tissue loss treated with epidermato-fascial osteoplasty according to Umiarov.

Treatment of tibial infected non-unions with bone and soft tissue loss has to solve three problems: infection, lack of bone continuity and lack of skin coverage. The aims of treatment are infection healing, bone consolidation with preservation of limb length and soft tissue reconstruction. The most important stage in the planning is an accurate débridement. Soft tissue reconstruction can be achieved using plastic surgery, and bone reconstruction is accomplished with bone grafts or induced membrane technique, but these methods may present disadvantages and risks. Epidermato-fascial osteoplasty is a modified procedure of compression-distraction osteosynthesis that was first described by Umiarov in 1982. This procedure offers the advantages of exactly classifying the phases of simultaneous bone and soft tissue regeneration, and of eliminating large tissue losses without previous closure of soft tissues or use of grafts, because the transported fragment takes fascia and skin along during the transport and closes the edges of the soft tissue gap until the epidermic and fascial reconstruction is complete. A total of 120 patients underwent this kind of surgery between 1986 and 2010 and were followed up for 2-26 years. Average age was 34 years (range 21-57 years). Cultures were positive for Staphylococcus in all cases, and for Pseudomonas in 27 cases. Adequate antibiotic therapy was administered in collaboration with the Infectious Diseases Specialist. Tibial bone resection was from 6 to 18cm (average 9.5cm). The Ilizarov apparatus was used with the oblique wire technique for bone transport in all patients. No intraoperative complications were observed. One patient died 40 days after the operation because of pulmonary embolism. The duration of treatment for the remaining 119 patients was 7-18 months. In all cases, infection eradication, healing of regenerate bone, consolidation at the docking site (with the aid of an autoplastic bone graft in only 11 patients), and epidermic and fascial reconstruction were observed, and functional results were very good. These techniques are particularly demanding for the patient and for the surgical team, but our results demonstrate that they can provide excellent outcomes in the management of difficult cases of infected non-unions.

Stable expression and functional characterization of a human nicotinic acetylcholine receptor with α6ß2 properties: discovery of selective antagonists.

BACKGROUND AND PURPOSE: Despite growing evidence that inhibition of α6ß2-containing (α6ß2*) nicotinic acetylcholine receptors (nAChRs) may be beneficial for the therapy of tobacco addiction, the lack of good sources of α6ß2*-nAChRs has delayed the discovery of α6ß2-selective antagonists. Our aim was to generate a cell line stably expressing functional nAChRs with α6ß2 properties, to enable pharmacological characterization and the identification of novel α6ß2-selective antagonists. EXPERIMENTAL APPROACH: Different combinations of the α6, ß2, ß3, chimeric α6/3 and mutant ß3(V273S) subunits were transfected in human embryonic kidney cells and tested for activity in a fluorescent imaging plate reader assay. The pharmacology of rat immune-immobilized α6ß2*-nAChRs was determined with ¹²5I-epibatidine binding. KEY RESULTS: Functional channels were detected after co-transfection of α6/3, ß2 and ß3(V273S) subunits, while all other subunit combinations failed to produce agonist-induced responses. Stably expressed α6/3ß2ß3(V273S)-nAChR pharmacology was unique, and clearly distinct from α4ß2-, α3ß4-, α7- and α1ß1δε-nAChRs. Antagonist potencies in inhibiting α6/3ß2ß3(V273S) -nAChRs was similar to their binding affinity for rat native α6ß2*-nAChRs. Agonist affinities for α6ß2*-nAChRs was higher than their potency in activating α6/3ß2ß3(V273S)-nAChRs, but their relative activities were equivalent. Focussed set screening at α6/3ß2ß3(V273S)-nAChRs, followed by cross-screening with the other nAChRs, led to the identification of novel α6ß2-selective antagonists. CONCLUSIONS AND IMPLICATIONS: We generated a mammalian cell line stably expressing nAChRs, with pharmacological properties similar to native α6ß2*-nAChRs, and used it to identify novel non-peptide, low molecular weight, α6ß2-selective antagonists. We also propose a pharmacophore model of α6ß2 antagonists, which offers a starting point for the development of new smoking cessation agents.

5-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors. Part 3.

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.

Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.

Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045).

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor.

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.

1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: a new series of potent and selective triple reuptake inhibitors.

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

Evaluation of bone density in infancy and adolescence. Review of medical literature and personal experience.

The evolution of medical and surgical therapies allows the increased survival rate of a growing number of children affected by rare pathologies. In this light osteoporotic disease is also of orthopaedic interest as it is sometimes the outward manifestation of serious pathologies (i.e. osteogenesis imperfecta). Sometimes, even in infancy and adolescence, osteoporosis is associated with complications due to fractures; in other cases it seems to have no immediate consequence. Nevertheless it must be considered as a fracture risk factor in adulthood as it negatively affects the achievement of peak bone mass. The evaluation of variations in bone mass that take place during growth is thus of particular importance in order to guarantee a level of bone health suitable for the next phase. These remarks compose the premise of a study on bone resistance carried out on a study population of between 6 and 18 years of age in the city of Pavia. To determine the resistance of the bone an ultrasound device was employed (Omnisense™ , Sunlight Medical Ltd, Tel Aviv, Israel) in two skeletal sites, distal radius and midshaft of tibia. The analysis of our results and a review of the relevant literature indicate that the median values of normality, against which we compare the measurements of the patients under examination, depend not only on age, sex, skeletal sites, race, and even ethnic group. The introduction of this new parameter, to be kept in mind when interpreting the results, invites us to be very prudent in determining the diagnostic threshold values in paediatric age. As with anthropometric data (weight, height, cranial circumference) it is possible to suggest an interpretation of the patient's SOS values comparing them with the 'centile curves' typical to the region the child belongs to. Of course, further studies are required to understand what are the variables involved and to determine the extension of the geographical area to be examined to obtain suitable reference curves.

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors--part II.

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.

6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors.

Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.

Phenylethynyl-pyrrolo[1,2-a]pyrazine: a new potent and selective tool in the mGluR5 antagonists arena.

The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.

Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain.

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.

Synthesis and SAR of substituted tetrahydrocarbazole derivatives as new NPY-1 antagonists.

The SAR of a new series of tetrahydrocarbazole derivatives is described: the appropriate decoration of this template led to the identification of a new class of NPY-1 antagonists showing good in vitro potency and a promising in vivo pharmacokinetic profile in rat.