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Introduction The incidence of anterior cruciate ligament (ACL) tears in skeletally immature patients has acutely increased over the last 20 years, yet there is no consensus on a single "best treatment". Selection of an optimal treatment is critical and based on individual circumstances; consequently, we propose a treatment-selection algorithm based on (i) skeletal development, (ii) ACL tear location, type, and quality, as well as (iii) parental perspective in order to facilitate the decision-making process. Evidence acquisition We combined our surgical group's extensive case histories of ACL tear management in Tanner Stage 1 and 2 patients with those in the literature to form a consolidated data base. For each case (i) the diagnostic phase, (ii) communication with patient and parents, (iii) treatment choice(s), (iv) selected surgical techniques and (v) rehabilitation schedule were critically analyzed and compared for patient outcomes. Evidence synthesis MRI-imaging and intraoperative tissue quality assessment were preeminent in importance for selection of the optimal treatment strategy. Considerations for selecting an optimal treatment included: (i) associated lesions, (ii) the child/patient and parent(s)' well-informed and counseled consent, (iii) biological potential, and (iv) the potential for successful ACL preservative surgery. Complete ACL tears were evaluated according to tear-location. In Type I and II ACL tears with remaining good tissue quality, we propose primary ACL repair. In Type III and IV ACL tears we propose physeal-sparing reconstruction with an iliotibial band graft. Finally, in the case of a Type V ACL tear, we propose that the best treatment be based on the Meyers-McKeever classification. Conclusions We present a facile decision-making algorithm for ACL management in pediatric patients based on specific elements of tissue damage and status.

Osteochondroma is one of the most common benign bone tumors; however, as it rarely affects any bones in feet, it may easily escape detection without rigorous examination. We present an exceptionally rare case of tarsal navicular dorsal osteochondroma diagnosed in an 11-year-old female child affected by chronic foot pain. Radiographs, MRI, and computed tomography scan revealed bony excrescences extending outward from the navicular bone. After conservative treatment failed, the navicular dorsal exostosis was excised in open surgery with complete resolution of symptoms. Navicular-cuneiform impingement was diagnosed by instrumental and intraoperative techniques. Histological analysis confirmed the diagnosis of navicular dorsal osteochondroma. This case report illustrates the necessity of particularly rigorous evaluation of the substrates of pediatric chronic foot pain.

The intra-articular synovial fluid environment in skeletally immature patients following an ACL tear is complex and remains undefined. Levels of inflammatory and anti-inflammatory cytokines change significantly in response to trauma and collectively define the inflammatory environment. Of these factors the resolvins, with their inherent anti-inflammatory, reparative, and analgesic properties, have become prominent. This study examined the levels of resolvins and other cytokines after ACL tears in skeletally immature and adult patients in order to determine if skeletal maturity affects the inflammatory pattern. Skeletally immature and adult patients with an anterior cruciate ligament injury and meniscal tears were prospectively enrolled over a 5-month period. Synovial fluid samples were obtained before surgery quantifying Resolvin E1, IL-1β, TNF-α, and IL-10 by ELISA. Comparisons between skeletally immature patients and adults, the influence of meniscal tear, growth plate maturity and time from trauma were analyzed. Skeletally immature patients had significantly greater levels of Resolvin E1 and IL-10 compared with adults with an isolated anterior cruciate ligament lesion. Among the injured skeletally immature patients Resolvin E1 levels were greater in the open growth plate group compared with those with closing growth plates. Moreover, levels of Resolvin E1 and IL-10 appeared to decrease with time. Our results suggest that skeletally immature patients have a stronger activation of the Resolvin pattern compared to adult patients and that synovial fluid Resolvins could play an antinflammatory role in the knee after anterior cruciate ligament lesion and that its activity may be synergistic with that of IL-10.

Introduction: Acute respiratory distress syndrome (ARDS) is an acute form of diffuse lung injury characterized by (i) an intense inflammatory response, (ii) increased pulmonary vascular permeability, and (iii) the loss of respiratory pulmonary tissue. In this article we explore the therapeutic potential of hexarelin, a synthetic hexapeptide growth hormone secretagogue (GHS), in an experimental model of ARDS. Hexarelin has anti-inflammatory properties and demonstrates cardiovascular-protective activities including the inhibition of cardiomyocyte apoptosis and cardiac fibrosis, both of which may involve the angiotensin-converting enzyme (ACE) system. Methods: In our experimental model, ARDS was induced by the instillation of 100 mM HCl into the right bronchus; these mice were treated with hexarelin (320 μg/kg, ip) before (Pre) or after (Post) HCl challenge, or with vehicle. Respiratory system compliance, blood gas analysis, and differential cell counts in a selective bronchoalveolar lavage (BAL) were determined 6 or 24 hours after HCl instillation. In an extended study, mice were observed for a subsequent 14 days in order to assess lung fibrosis. Results: Hexarelin induced a significant improvement in lung compliance and a reduction of the number of total immune cells in BAL 24 hours after HCl instillation, accompanied with a lower recruitment of neutrophils compared with the vehicle group. At day 14, hexarelin-treated mice presented with less pulmonary collagen deposition compared with vehicle-treated controls. Conclusions: Our data suggest that hexarelin can inhibit the early phase of the inflammatory response in a murine model of HCl-induced ARDS, thereby blunting lung remodeling processes and fibrotic development.

Purpose The aim of this study was to assess midterm clinical outcomes in Tanner 1–2 patients with proximal anterior cruciate ligament (ACL) tears following arthroscopic-surgical repair using an absorbable or an all-suture anchor. Methods Fourteen (9.2 ± 2.9 years-old) of 19 skeletally immature patients reached the 2 years of clinical follow-up. Physical examinations included the Lachman test, Pivot-shift test, One-leg Hop test, Pedi-IKDC as well as Lysholm and Tegner activity scores; knee stability was measured with a KT-1000 arthrometer. Overall re-rupture rates were also evaluated in all operated patients. Results At 2 years post-surgery, the Lysholm score was 93.6 ± 4.3 points, and the Pedi-IKDC score was 95.7 ± 0.1. All patients returned to the same sport activity level as prior to ACL lesion within 8.5 ± 2.9 months, with one exception who reported a one-point reduction in their Tegner Activity score. No leg-length discrepancies or malalignments were observed. Four patients presented grade 1 Lachman scores, and of these, three presented grade 1 (glide) score at Pivot-shift; clinical stability tests were negative for all other patients. Anterior tibial shift showed a mean side-to-side difference of 2.2 mm (range 1–3 mm). The One-leg Hop test showed lower limb symmetry (99.9% ± 9.5) with the contralateral side. Overall, 4 out of 19 patients presented a re-rupture of the ACL with a median time between surgery and re-rupture of 3.9 years (range 1–7). Conclusion This surgical technique efficiently repairs proximal ACL tears, leading to a restoration of knee stability and a quick return to an active lifestyle, avoiding growth plate disruption. Level of evidence IV.

Background In children, fracture non-union is uncommon yet, curiously, non-union of distal fibula fractures are rarely reported. Historically, the most common treatment of a lateral malleolus fracture after an ankle sprain is conservative, which usually leads to fracture union. However, even in clinically stable ankles, subsequent pain arising from fracture site could suggest non-union, thereby necessitating reexamination and possible secondary treatment. Case presentation We report the case of an 8-year-old girl with an epiphyseal distal fibula fracture complicated with a symptomatic non-union associated with the chondral flap of the talar dome after conservative treatment. Surgical excision of the fragment and chondroplasty was performed and resulted in an excellent clinical outcome. Conclusion This case report illustrates the necessity of particularly meticulous evaluation of pediatric post-traumatic ankle pain. Surgical treatment as well as talar chondral evaluation should be taken into consideration in the treatment of pediatric distal fibular nonunion.

The specific etiology of meniscal tears, including the mechanism of lesion, location, and orientation, is considered for its contribution to subsequent joint cytokine responsiveness, healing outcomes, and by extension, appropriate lesion-specific surgical remediation. Meniscal repair is desirable to reduce the probability of development of posttraumatic osteoarthritis (PTOA) which is strongly influenced by the coordinate generation of pro- and anti-inflammatory cytokines by the injured cartilage. We now present biochemical data on variation in cytokine levels arising from two particular meniscal tears: bucket-handle (BH) and posterior horn (PH) isolated meniscal tears. We selected these two groups due to the different clinical presentations. We measured the concentrations of TNF-α, IL-1β, IL-6, IL-8, and IL-10 in knee synovial fluid of 45 patients with isolated meniscal lesions (BH tear, n = 12 ; PH tear, n = 33 ). TNF-α levels were significantly ( p < 0.05 ) greater in the BH group compared with the PH group, whereas IL-1β levels were significantly greater ( p < 0.05 ) in the PH group compared with the BH group. Both BH and PH groups were consistent in presenting a positive correlation between concentrations of IL-6 and IL-1β. A fundamental difference in IL-10 responsiveness between the two groups was noted; specifically, levels of IL-10 were positively correlated with IL-6 in the BH group, whereas in the PH group, levels of IL-10 were positively correlated with IL-1β. Collectively, our data suggest a possible influence of the meniscal tear pattern to the articular cytokine responsiveness. This differential expression of inflammatory cytokines may influence the risk of developing PTOA in the long term.

Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.

Introduction: This study evaluates mid-term results of acetabular revision using a hemispherical acetabular cup in Trabecular Titanium with a cage construct. Methods: We reviewed 36 acetabular revisions performed with the Delta Revision TT cup in 34 patients (mean age = 75, range: 45–92 years). Acetabular defect types (Paprosky classification) included (1) 2B ( n = 5), (2) 2C ( n = 7), (3) 3A ( n = 15), and (4) 3B ( n = 9). Morcellised bone allografts were used in 24 cases, and synthetic bone used in 11. Outcomes were evaluated using the Harris Hip Score (HHS), and the Verbal Rating Scale (VRS) for pain measurement. X-ray visualisation of cup position was used to discern signs of mobilisation and bone graft incorporation. Survivorship at post-revision follow-up (mean = 39.8; range 12–91.5 months) was calculated. Results: HHS increased from 40.5 to 87 ( p < 0.01). 68% of cases were pain free; by comparison, 32% had an average VRS score of 1.9 (range 1–3). The average cup inclination angle was 40.8° (30–52°) postoperatively, compared with 41.2° (30–52°) at follow-up; there were no signs of loosening or mobilisation. Centre of rotation was fully restored in 21 (58.3%) hips. According to Gie classification; bone graft incorporation grades were (1) 3 ( n = 21), (2) 2 ( n = 12) and (3) 1 ( n = 2). The survival rate was 100% for aseptic loosening and 91.7% for any cause of revision. Conclusions: The Delta Revision TT cup promises good clinical and radiographic results at short- to mid-term follow-up, with high rates of survival rate and bone integration.

Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, long-term safety and efficacy of androgen administration has yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe and economical. There are, however, few clinical studies, which have focused on effects of androgen therapy on pre- and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological tissues.

TLQP-21, a peptide encoded by the prohormone VGF, is expressed in neuroendocrine cells and can modulate inflammatory processes. Since TLQP-21 can bind the complement 3a receptor 1 on macrophages, interest has risen in this peptide as a potential drug for the treatment of Acute Respiratory Distress Syndrome (ARDS), whose hospital mortality can reach 35–46%. Since no effective pharmacologic therapies are available, our aim was to exploit the potential of a short analog of TLQP-21(JMV5656) in order to modulate the inflammatory process in ARDS and the progression to pulmonary fibrosis in an experimental model of unilateral acid aspiration in mice. Mice were divided in 2 treatment groups. In the acute protocol, mice received intra-peritoneal injection of either vehicle or 0.6 mg/kg JMV5656 on experimental days 1 and 2, and ARDS was induced on day 3 under deep anesthesia by instillation of HCl (1.5 ml/kg of 0.1 M HCl in 0.9% NaCl) into the right lung; all measurements were performed 24 h later. In the subacute protocol, mice were treated as previously, but treatment with vehicle or JMV5656 was repeated also on day 4 and measurements were made 2 weeks later. Twenty-four hours after acid instillation, the total number of immune cell in the BAL rose sharply due primarily to an increase in the PMN population which increased from 1% up to 58% of total cell numbers. JMV5656 significantly reduced PMN recruitment into the alveolar space, but had no effects on cytokine levels in BAL. Two weeks after acid injury, static compliance of the right lung was significantly higher in the JMV5656-treated group compared to vehicle-treated group. Treatment with JMV5656 also blunted the acid-induced collagen deposition in the right lung. These results suggest that JMV5656 can ameliorate mechanical compliance, and reduce collagen deposition in acid-injured lungs in mice. This effect was likely due to the ability of JMV5656 to inhibit PMN recruitment in the injured lung.

Introduction: Ideal treatment of acute acromioclavicular joint (ACJ) dislocation remains unresolved. We evaluated ACJ reconstruction using polyester tapes and temporary Kirschner wire (KW) and presented clinical and radiological outcomes. Materials and methods: Patients were retrospectively evaluated and classified according to Rockwood classification, clinical and sportive characteristics. Constant Score (CS) and ACJ joint instability (ACJI) score were collected. Zanca’s, Alexander, axillary, standard, and stress AP views were collected. Radiographic coracoclavicular distance (CCd) of healthy and injured shoulders was measured pre-operatively, at 3months and at minimum 2-year follow-up. Heterotopic ossifications and clavicular osteolysis were evaluated. Influence of patients’ characteristics and AC joint type on clinical and radiological outcomes were determined. Results: Sixteen patients (13 type V and 3 type III ACJ dislocation) reached the end of follow-up (mean 2.4years; range 22–72months). Mean CS was 99.63 (range 96–100), while the mean ACJI score was 96.19 (range 85–100). The CCd of the treated shoulder was comparable with the healthy shoulder at 3months and at last follow-up; moreover, there was no difference in CCd scores at 3months and at 2years. CCd scores were lower in sedentary patients compared with physically active (sporty) patients. Heterotopic ossifications were observed in three patients. No osteolysis was reported. Conclusion: This technique provides good results with few complications and should be considered as an effective method to treat ACJ acute dislocation. CCd scores correlate with overuse factors but not with other clinical scores.

Concentrations of pro- and anti-inflammatory cytokines in synovial fluid samples collected from patients with chronic meniscal tears were investigated. An acute inflammatory response is generally reported 24-48 h after knee injury, but the largest body of data available in literature concerns anterior cruciate ligament injury and very little information is available about the balance of soluble factors in the synovial fluid of knees with chronic meniscal tears. Sixty-nine patients (46 males and 23 females) with meniscal tear that occurred more than 3 months earlier were enrolled. According to cartilage integrity assessment by arthroscopic examination, patients were assigned to one of the following groups: (i) no chondral damage (n = 18); (ii) chondral damage graded from I to II (n = 15); and (iii) chondral damage graded from III to IV (n = 37). In all groups, levels of IL-10 and inflammatory cytokines IL-6, TNF-α, and IL-8 where greater compared with those reported in the intact population; by contrast, levels of IL-1ra and IL-1β were significantly lower. Interestingly, IL-6 levels were higher in female than male patients. Cytokine levels did not correlate with degree of chondral damage. IL-6 and IL-1ra levels positively correlated with IL-1β, and negatively correlated with TNF-α. Interestingly, levels of IL-1β and TNF-α were inversely correlated. Our data demonstrate increased levels of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α) in the chronic phase of meniscal trauma. This pro-inflammatory state is maintained in the joint from the time of initial injury to several months later and could be a key factor in hampering cartilage regeneration. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:340-346, 2017.

The treatment of anterior cruciate ligament (ACL) injuries in children and adolescents is challenging. Preclinical and clinical studies investigated ACL repairing techniques in skeletally immature subjects. However, intra-articular bioenvironment following ACL tear has not yet been defined in skeletally immature patients. The aim of this study was to measure cytokine concentrations in the synovial fluid in adolescent population. Synovial levels of IL-1β, IL-1ra, IL-6, IL-8, IL-10, and TNF-α were measured in 17 adolescent patients (15 boys) with ACL tears who underwent ACL reconstruction including acute (5), subacute (7), and chronic (5) phases. Femoral growth plates were classified as “open” in three patients, “closing” in eight, and “closed” in six. Eleven patients presented an ACL tear associated with a meniscal tear. The mean Tegner and Lysholm scores (mean±SD) of all patients were 8 ± 1 and 50.76 ± 26, respectively. IL-8, TNF-α, and IL-1β levels were significantly greater in patients with “open” physes. IL-1ra and IL-1β levels were significantly higher in patients with ACL tear associated with a meniscal tear. Poor Lysholm scores were associated with elevated IL-6 and IL-10 levels. IL-10 levels positively correlated with IL-6 and IL-8 levels, whereas TNF-α concentration negatively correlated with IL-6 levels. Skeletally immature patients with meniscal tears and open growth plates have a characteristic cytokine profile with particularly elevated levels of proinflammatory cytokines including IL-8, TNF-α, and IL-1β. This picture suggests that the ACL tear could promote an intra-articular catabolic response in adolescent patients greater than that generally reported for adult subjects. The study lacks the comparison with synovial samples from healthy skeletally immature knees due to ethical reasons. Overall, these data contribute to a better knowledge of adolescent intra-articular bioenvironment following ACL injuries.

Oncologic patients subjected to chemotherapy frequently present aphagia, malnutrition, and cachexia. The purpose of this study was to investigate whether selected growth hormone secretagogues including hexarelin, JMV2894 and JMV2951 could antagonize body weight loss and wasting induced by cisplatin administration in rats. The three growth hormone secretagogues behaved as full agonists of the growth hormone secretagogues receptor both in terms of ability to stimulate calcium mobilization in Chinese hamster ovary cells and stimulation of growth hormone release in neonatal rats. Adult rats were (i) treated with vehicle throughout (controls), or (ii) treated with cisplatin (days 1–3) and a growth hormone secretagogues or vehicle, (days 1–12). Body weight and food consumption were measured daily. Although all growth hormone secretagogues caused initial transient acute increases in food intake, the total amount of food eaten by controls and growth hormone secretagogues treated groups over the 12 experimental days was not significantly different. All groups pre-treated with cisplatin lost up to 5–10 % body weight in the first 4 days; they subsequently gained weight at a rate comparable with controls. Interestingly, rats which received JMV2894 demonstrated a faster gain in body weight than any other growth hormone secretagogues treated group and at the end of the protocol reached a weight similar to that of controls. JMV2894 did not stimulate perirenal and epididymal fat accumulation but reduced MuRF mRNA levels in skeletal muscles. In conclusion, our findings demonstrate that JMV2894 antagonizes cisplatin induced weight loss in rats and may prove useful in antagonizing cachexia associated with cancer and chemotherapy in humans.

Anterior cruciate ligament (ACL) reconstruction restores knee stability but does not reduce the incidence of posttraumatic osteoarthritis induced by inflammatory cytokines. The aim of this research was to longitudinally measure IL-1β, IL-6, IL-8, IL-10, and TNF-αlevels in patients subjected to ACL reconstruction using bone-patellar tendon-bone graft. Synovial fluid was collected within 24–72 hours of ACL rupture (acute), 1 month after injury immediately prior to surgery (presurgery), and 1 month thereafter (postsurgery). For comparison, a “control” group consisted of individuals presenting chronic ACL tears. Our results indicate that levels of IL-6, IL-8, and IL-10 vary significantly over time in reconstruction patients. In theacute phase,the levels of these cytokines in reconstruction patients were significantly greater than those in controls. In thepresurgeryphase, cytokine levels in reconstruction patients were reduced and comparable with those in controls. Finally, cytokine levels increased again with respect to control group in thepostsurgeryphase. The levels of IL-1βand TNF-αshowed no temporal variation. Our data show that the history of an ACL injury, including trauma and reconstruction, has a significant impact on levels of IL-6, IL-8, and IL-10 in synovial fluid but does not affect levels of TNF-αand IL-1β.

Surgical reconstruction of the anterior cruciate ligament (ACL) does not necessarily decrease the risk of developing osteoarthritis (OA). The inflammatory response and relative changes in pro- and anti-inflammatory cytokines could participate in triggering the development of OA. To test this hypothesis we measured the concentrations of IL-1β, IL-1ra, IL-6, IL-8, IL-10, and TNF-α at different times after ACL rupture. The sample population consisted of 48 patients with ACL tear which were assigned to different groups according to the time elapsed from the injury: 22 acute (A), 7 early sub-acute (ESA), 11 late sub-acute (LSA), and 8 chronic (C). In group A, there were high levels of IL-1β, IL-6, and IL-8, whereas levels of IL-1ra and TNF-α were significantly lower than usually reported. IL-1β and IL-8 concentrations returned with time to normal levels in the ESA group. Interestingly, IL-1ra levels remained always significantly lower than normally reported levels, and TNF-α levels did not increase after trauma. Our data show increased level of pro-inflammatory cytokines (IL-6 and IL-8) in the acute phase of inflammation which could be responsible for triggering cartilage catabolism and suggest that prompt neutralization of IL-6 and IL-8 accumulations in synovial fluid could help prevent development of OA in ACL-injured knees.

The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβin vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.