Arthroscopic Latarjet for Primary Shoulder Instability With Off-Track Lesions or Revision Surgery Yields Satisfactory Clinical Results and Reliable Return to Sport and Work at Minimum 3-Year Follow-Up.

PURPOSE: To retrospectively evaluate clinical and radiologic outcomes and return to sport and to work of patients after arthroscopic Latarjet stabilization for primary instability or revision surgery; factors influencing and determining results and potential predictors for clinical outcomes also were evaluated. METHODS: This is a retrospective study including patients older than 18 years old who underwent arthroscopic Latarjet stabilization for recurrent anterior glenohumeral instability with off-track lesions, or for cases of recurrence after previous surgery, from 2011 to 2017. Patients were assessed preoperatively and at a minimum 3 years of follow-up using the Rowe score, the University of California at Los Angeles Shoulder Score and Simple Shoulder Test score; the range of motion, satisfaction rate, return to work and sport, perception of discomfort during sporting and daily activities, and complications and recurrence after surgery were also evaluated. The integration of the coracoid graft and the position of the screws were examined by computed tomography scan. RESULTS: At a mean follow-up time of 6 ± 2 years, 93 patients (95 shoulders) showed significant improvement of all scale scores (P < .001), 97.8% of the patients had returned to the same working condition as before surgery, and all the patients who practiced sports preoperatively (85; 91.4%) returned to sport after surgery; 97.9% of patients were satisfied with surgery. The complication rate was 5.4%, and 2 cases (2.1%) of recurrence occurred, both after high-energy trauma. At an average of 17 ± 13 months postoperatively, computed tomography scans showed 4 (6.6%) stable nonunions, 9 (14.8%) superior, and 1 (1.6%) inferior lyses of the graft; a correct positioning of the graft was observed in 86.9% of the cases. Greater satisfaction, fewer complications, less pain during daily activities, and a lower number of reoperations were associated with a shorter time between the first dislocation episode and surgery (P = .019, P < .001, P = .014, and P = .005, respectively). Complications were directly associated with older patient age at operation (P = .001). A greater number of nonunions was found in patients with increased angle between the line linking the posterior and anterior glenoid rim and the screw axis (P = .040) and a medial axial position or a lower coronal position of the graft (both P = .010). A lower age at the time of surgery predicted better Rowe scores at follow-up (P < .001), and a lower age at the time of the first episode of dislocation predicted better postoperative Simple Shoulder Test scores (P = .026). CONCLUSIONS: At a mean 6-year follow-up time, excellent clinical outcomes, and radiological results, with few complications, high rates of satisfaction and return to work and sport and low sports anxiety can be expected after arthroscopic Latarjet procedure. A shorter time between the first dislocation episode and surgery was associated with higher satisfaction, fewer complications, less pain during daily activities and lower reoperations; a lower age at the operation was associated with lower complications.

Early traumatic experiences impair the functioning of both components of the endogenous stress response system in adult people with eating disorders.

Childhood trauma is a non-specific risk factor for eating disorders (EDs). It has been suggested that this risk is exerted through trauma-induced long-lasting changes in the body stress response system. Therefore, we explored the activity of the hypothalamus-pituitary-adrenal axis and of the sympathetic nervous system in adult ED patients with or without a history of childhood trauma exposure. Salivary cortisol and alpha-amylase, a marker of the sympathetic nervous system activity, were measured at awakening and after 15, 30 and 60 min in 35 women with EDs. The Childhood Trauma Questionnaire (CTQ) was employed to assess exposure to childhood trauma and, according to the CTQ cut-off scores, 21 ED women were classified as maltreated (Mal) participants and 14 women as no-maltreated (noMal) ED participants. Compared to noMal ED women, Mal ED participants showed significantly decreased cortisol awakening response (between group difference: p = 0.0003) and morning salivary alpha-amylase secretion (between group difference: p = 0.02). Present results confirm that the cortisol awakening response of adult ED patients with childhood trauma exposure is lower than that of adult ED patients without childhood trauma experiences and show for the first time that also the morning secretion of salivary alpha-amylase is decreased in adult ED patients who have been exposed to early traumatic experiences. These results point for the first time to a dampening in the basal activity of both components of the endogenous stress response system in childhood maltreated adult ED women.

A network analysis of psychological, personality and eating characteristics of people seeking bariatric surgery: Identification of key variables and their prognostic value.

OBJECTIVE: The interplay among personality traits, anxiety and eating symptoms in candidates for bariatric surgery has never been investigated through the network analysis approach. Thus, we aimed to use this method to identify the key psychological traits that characterize these individuals and to assess their role as predictors of surgical outcomes. METHODS: One-hundred-eighty-five candidates for bariatric surgery filled in the State Trait Anxiety Inventory (STAI), the Revised Restraint Scale, the Power of Food Scale and the Temperament and Character Inventory-Revised (TCI-R) questionnaires. All these variables were included in a network analysis. Then, the most central network nodes were entered as independent variables in a regression model that included 9-month follow-up weight outcomes as the dependent variable. RESULTS: The network has showed a good stability. TCI-self directedness and harm avoidance scores and STAI state and trait anxiety scores were the nodes with the highest centrality in the network. Weight outcomes were assessed in 64 patients at follow-up. Among central nodes, low TCI-self directedness was found to be the only significant independent predictor of worse weight outcome. CONCLUSIONS: Our findings show for the first time the interplay between personality traits and symptoms in candidates for bariatric surgery combining the network approach with a follow-up evaluation. Low self-directedness has been proved to be the node with highest centrality and the only predictor of short-term weight outcome. These data suggest the importance to take into consideration personality and psychological variables either in the pre-surgery assessment or as possible targets for pre or post-surgery psychotherapeutic interventions. ORCID: 0000-0002-6786-4458.

Deranged emotional and cortisol responses to a psychosocial stressor in anorexia nervosa women with childhood trauma exposure: Evidence for a "maltreated ecophenotype"?

Exposure to trauma in the childhood and abnormal interpersonal stress reactivity are believed to contribute to the pathophysiology of anorexia nervosa (AN), which suggests a possible role of the hypothalamus-pituitary adrenal (HPA) axis. Although an effect of early traumatic experiences on the cortisol awakening response has been proved in patients with AN, the consequences of childhood trauma exposure on HPA axis reactivity to psychosocial stressors has been never investigated in such individuals. Therefore, we have assessed emotional and cortisol responses to an acute psycho-social stress in AN patients with a history of childhood trauma exposure. Twenty-four AN women and 17 healthy women were enrolled in the study. Patients were classified as maltreated (Mal) or non-maltreated (noMal) according to their Childhood Trauma Questionnaire scores. Participants underwent the Trier Social Stress Test (TSST) and their emotional responses were measured through the state scale of the State-Trait Anxiety Inventory. Saliva samples were collected to measure cortisol production. Compared to both healthy subjects and noMal AN patients, Mal AN women exhibited a blunted cortisol response to TSST. With respect to healthy controls, pre-TSST anxiety levels were enhanced in both AN groups; moreover, Mal AN patients displayed a reduced anxiety increase after TSST as compared to both noMal patients and healthy women. Our findings for the first time provide the evidence of deranged biological and emotional responses to an acute social stress in AN patients with childhood trauma exposure, corroborating the idea of a maltreated ecophenotype in AN as in other psychiatric disorders.

Wnt/ß-Catenin Signaling Induces Integrin α4ß1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice.

The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4+ T cells in the CNS are not known. In this article, we report that abnormal ß-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced ß-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4ß1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of ß-catenin in mature naive T cells was sufficient to drive integrin α4ß1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4ß1 reduced the abnormal T cell presence in the CNS of ß-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/ß-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

Ghrelin response to hedonic eating in underweight and short-term weight restored patients with anorexia nervosa.

Recently, anorexia nervosa (AN) has been conceptualized as a reward-related disorder, and alterations in brain reward processes have been documented in both acute and recovered AN patients. However, the role of endogenous biochemical mediators, such as ghrelin, in the modulation of reward processes has been poorly investigated in this eating disorder. Hedonic eating, that is the consumption of food exclusively for pleasure and not to maintain energy homeostasis, is a useful paradigm to investigate the physiology of food-related reward. Therefore, we assessed the response of peripheral ghrelin to hedonic eating in 7 underweight and 7 recently weight-restored AN patients and compared it to that of previously studied healthy controls. We found that in satiated underweight patients with AN plasma ghrelin levels progressively decreased after the exposure and the consumption of both the favorite and unfavorite food whereas in satiated weight-restored AN patients and satiated healthy controls plasma ghrelin concentrations significantly increased after the exposure to the favorite food and after eating it, but decreased after the unfavorite food. These results suggest a derangement in the ghrelin modulation of food-related pleasurable and rewarding feelings, which might sustain the reduced motivation toward food intake of acute AN patients.

Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice.

Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220(+) cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B cell-specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders.

Recombinant long-glucocorticoid-induced leucine zipper (L-GILZ) protein restores the control of proliferation in gilz KO spermatogonia.

No genes are yet directly implicated in etiology of male infertility. Identification of genes critical at various stages of spermatogenesis is pivotal for the timely diagnostic and treatment of infertility. We previously found that L-GILZ deficiency in a mouse KO model leads to hyperactivation of Ras signaling and increased proliferation in spermatogonia, resulting in male sterility. The possibility to establish culture cell system that maintains spermatogonial cells in vitro allowed us to delivery a recombinant protein TAT-L-GILZ able to restore normal proliferation rate in gilz KO spermatogonia. We also found that N-terminal part of L-GILZ protein is responsible for Ras/L-GILZ protein-to-protein interaction, important for the control of proliferation rate of spermatogonia. Therefore, treatments increasing L-GILZ expression, such as delivering small molecules or peptides that mimic L-GILZ functions, are approaches with great potential of applicability for new therapeutic strategies based on gene/protein delivery to the affected testes.

GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF-ß signaling.

Regulatory T (Treg) cells expressing the transcription factor forkhead box P3 (FoxP3) control immune responses and prevent autoimmunity. Treatment with glucocorticoids (GCs) has been shown to increase Treg cell frequency, but the mechanisms of their action on Treg cell induction are largely unknown. Here, we report that glucocorticoid-induced leucine zipper (GILZ), a protein induced by GCs, promotes Treg cell production. In mice, GILZ overexpression causes an increase in Treg cell number, whereas GILZ deficiency results in impaired generation of peripheral Treg cells (pTreg), associated with increased spontaneous and experimental intestinal inflammation. Mechanistically, we found that GILZ is required for GCs to cooperate with TGF-ß in FoxP3 induction, while it enhances TGF-ß signaling by binding to and promoting Smad2 phosphorylation and activation of FoxP3 expression. Thus, our results establish an essential GILZ-mediated link between the anti-inflammatory action of GCs and the regulation of TGF-ß-dependent pTreg production.

Robotic single-site hysterectomy in low risk endometrial cancer: a pilot study.

BACKGROUND: To evaluate the feasibility and the safety of robotic single-site hysterectomy (RSSH) in low risk early endometrial cancer. METHODS: Patients with clinical low risk early endometrial cancer were enrolled onto a prospective cohort trial. All surgical procedures were performed through a single 2-2.5 cm umbilical incision, with a multichannel system consisting of a five-lumen port providing access for two single-site instruments (da Vinci Si Surgical System, Intuitive Surgical, Sunnyvale, CA), the 8.5 mm 3D HD endoscope, a 5/10 mm accessory port, and an insufflation adaptor. RESULTS: Between December 2011 and June 2012, a total of 17 patients were included in our pilot study. The median age of the patients was 64 years (range, 42-84 years), and median body mass index was 26.6 kg/m(2) (range, 18-52 kg/m(2)). One patient was excluded from the study as a result of pelvic metastasis during inspection of abdominal cavity, and another patient was converted to vaginal surgery as a result of problems of hypercapnia. The median docking time, console time, and total operative time was 8 min (range, 5-14 min), 48 min (range, 45-51 min), and 90 min (range, 70-147 min), respectively. The median blood loss was 75 mL (range, 50-150 mL). No laparoscopy/laparotomy conversion was registered. The median time to discharge was 2 days (range, 1-3 days). Neither intraoperative nor postoperative complications occurred. At a median of 7.5 months' follow-up, all patients were disease-free. CONCLUSIONS: RSSH is technically feasible in patients affected by low risk early endometrial cancer. Additional studies with gynecologic oncologic cases should be performed to explore the possible benefits of RSSH.

Robotic transperitoneal aortic lymphadenectomy in gynecologic cancer: a new robotic surgical technique and review of the literature.

BACKGROUND: Lymph node status is a prognostic factor for gynecologic cancer. We describe a new developing strategy for robotic transperitoneal aortic lymphadenectomy without relocating the robotic column or the patient. METHODS: Patients with histologically confirmed cervical cancer, early ovarian cancer, or endometrial carcinoma with suspected risk factors indicating aortic lymphadenectomy were eligible for the robotic transperitoneal aortic lymphadenectomy using the Da Vinci robotic system as part of the surgical treatment of gynecologic malignancies. RESULTS: The mean operating time was 224 min (range 160-300 min), and the mean console time for aortic lymphadenectomy was 43 min (range 30-75). The median hemoglobin fall was 1.3 g/dL range (0.8-2 g/dL), the median number of removed aortic lymph nodes was 12.5 (range 7-17), and the median length of the hospital stay was 2 days (range 1-4 days). We experienced an intraoperative complication, but no conversion to laparotomy was necessary. No patients received a blood transfusion. CONCLUSIONS: This initial experience demonstrates the feasibility of robotic aortic lymphadenectomy with good accuracy and safety without relocating the robotic column or the patient.

Robotic radical hysterectomy after neoadjuvant chemotherapy in locally advanced cervical cancer.

Neoadjuvant platinum-based chemotherapy (NACT) plus radical hysterectomy and pelvic lymphadenectomy has been demonstrated to be a valid alternative to chemoradiation in patients with advanced cervical cancer. Several publications have reported on the feasibility of robot-assisted laparoscopy in early cervical cancer. Herein is reported the case of a woman with locally advanced cervical cancer that was successfully treated using neoadjuvant chemotherapy followed by total robotic type C1 radical hysterectomy (TRRH) plus pelvic lymphadenectomy. The success of this approach, which is not the standard of care in this disease, suggests that additional studies should be performed in a selected population.

Helper-dependent adenovirus for the gene therapy of proliferative retinopathies: stable gene transfer, regulated gene expression and therapeutic efficacy.

BACKGROUND: Ocular neovascular disorders, such as diabetic retinopathy and age-related macular degeneration, are the principal causes of blindness in developed countries. Current treatments are of limited efficacy, whereas a therapy based on intraocular gene transfer of angiostatic factors represents a promising alternative. For the first time we have explored the potential of helper-dependent adenovirus (HD-Ad), the last generation of Ad vectors, in the therapy of retinal neovascularization. METHODS: We first analyzed efficiency and stability of intraretinal gene transfer following intravitreous injection in mice. A HD-Ad vector expressing green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) promoter (HD-Ad/GFP) was compared with a first-generation (E1/E3-deleted) Ad vector carrying an identical GFP expression cassette (FG-Ad/GFP). We also constructed HD-Ad vectors expressing a soluble form of the VEGF receptor (sFlt-1) in a constitutive (HD-Ad/sFlt-1) or doxycycline (dox)-inducible (HD-Ad/S-M2/sFlt-1) manner and tested their therapeutic efficacy upon intravitreous delivery in a rat model of oxygen-induced retinopathy (OIR). RESULTS: HD-Ad/GFP promoted long-lasting (up to 1 year) transgene expression in retinal Müller cells, in marked contrast with the short-term expression observed with FG-Ad/GFP. Intravitreous injection of HD-Ad vectors expressing sFlt-1 resulted in detectable levels of sFlt-1 and inhibited retinal neovascularization by more than 60% in a rat model of OIR. Notably, the therapeutic efficacy of the inducible vector HD-Ad/S-M2/sFlt-1 was strictly dox-dependent. CONCLUSIONS: HD-Ad vectors enable stable gene transfer and regulated expression of angiostatic factors following intravitreous injection and thus are attractive vehicles for the gene therapy of neovascular diseases of the retina.

Long-term and tight control of gene expression in mouse skeletal muscle by a new hybrid human transcription factor.

Diseases requiring frequent and lifelong injections of recombinant proteins would be more efficaciously treated by intramuscular delivery of genes encoding secretable proteins. However, the success of this approach largely depends on our capability to temporally regulate transcription of delivered genes. Therefore, we sought to generate a humanized transcription factor to regulate transgene expression in muscle. A novel 4-hydroxytamoxifen (4-OHT)-dependent transcriptional regulator (called HEA-3) was constructed by fusing in-frame the DNA binding domain of the human hepatocyte nuclear factor-1alpha (HNF1alpha), which is not expressed in muscle cells, a G(521)R mutant of the ligand binding domain of human estrogen receptor-alpha (ERalpha), and the activation domain derived from human nuclear factor-kappaB p65 subunit (NF-kappaB p65). We demonstrate that an artificial promoter containing multimeric HNF1alpha binding sites is silent in muscles and in cell lines that lack endogenous HNF1alpha. HEA-3 stimulated transcription from this target promoter in a stringent 4-OHT-dependent manner. The dynamic range of transgene regulation was high, because of the low basal activity and high inducibility of the system. Ex vivo, HEA-3 increased expression of the transfected reporter gene by more than 1000-fold in a ligand-dependent manner. In vivo, HEA-3 stimulated by more than 100-fold, the expression of secreted alkaline phosphatase after delivery as plasmid DNA into mouse muscles. Moreover, long-term modulation of the expression of intramuscularly delivered mouse erythropoietin was achieved in immunocompetent mice.