The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

Endosomal Rab cycles regulate Parkin-mediated mitophagy.

Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson's disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.

Reverse Shoulder Arthroplasty for the treatment of Proximal humeral fractures in the Elderly (ReShAPE trial) : study protocol for a multicentre combined randomised controlled and observational trial.

BACKGROUND: Proximal humeral fractures are common in older patients. The majority are minimally displaced and are associated with good outcomes after nonoperative treatment. Poorer outcomes are associated with displaced, multipart fractures. There is no clear benefit from surgical fracture fixation compared to nonoperative treatment. Replacement of the fractured humeral head with a hemiarthroplasty is another treatment option, but has not been shown to be clearly superior to nonoperative treatment or internal fixation. Recently, reverse total shoulder arthroplasty has been used to treat these fractures, particularly in the older population with several case series demonstrating good outcomes. No comparative trial has been performed to test the effectiveness of reverse total shoulder arthroplasty against nonoperative treatment. METHODS/DESIGN: ReShAPE (Reverse Shoulder Arthroplasty for the treatment of Proximal humeral fractures in the Elderly) is a multicenter combined randomized and observational study. The primary objective is to compare pain and function 12 months post fracture using the American Shoulder and Elbow Society (ASES) score in patients aged 70 years or older with three- and four-part proximal humeral fractures treated by either reverse shoulder arthroplasty or nonoperative treatment. Secondary outcome measures will include the DASH (Disability of the Arm, Shoulder and Hand) score, the EQ-5D (EuroQol Health Survey), the EQ-VAS, pain, radiological parameters and complications. DISCUSSION: The study will assess the effectiveness of reverse shoulder arthroplasty for complex proximal humeral fractures and thereby guide treatment of a common injury in the older population. TRIAL REGISTRATION: World Health Organization Universal Trial Number (WHO UTN): U1111-1180-5452 . Registered on 10 March 2016. Australian and New Zealand Clinical Trials Registry (ANZCTR): 12616000345482 . Registered on 16 March 2016.

The effects of low-intensity pulsed ultrasound on tendon-bone healing in a transosseous-equivalent sheep rotator cuff model.

PURPOSE: The purpose of this study was to examine the effects Low-intensity Pulsed Ultrasound has on initial tendon-bone healing in a clinically relevant extra-articular transosseous-equivalent ovine rotator cuff model. METHODS: Eight skeletally mature wethers, randomly allocated to either control group (n = 4) or treatment group (n = 4), underwent rotator cuff surgery following injury to the infraspinatus tendon. All animals were killed 28 days post surgery to allow examination of early effects of Low-intensity Pulsed Ultrasound treatment. RESULTS: General improvement in histological appearance of tendon-bone integration was noted in the treatment group. Newly formed woven bone with increased osteoblast activity along the bone surface was evident. A continuum was observed between the tendon and bone in an interdigitated fashion with Sharpey's fibres noted in the treatment group. Low-intensity Pulsed Ultrasound treatment also increased bone mineral density at the tendon-bone interface (p < 0.01), while immunohistochemistry results revealed an increase in the protein expression patterns of VEGF (p = 0.038), RUNX2 (p = 0.02) and Smad4 (p = 0.05). CONCLUSIONS: The results of this study indicate that Low-intensity Pulsed Ultrasound may aid in the initial phase of tendon-bone healing process in patients who have undergone rotator cuff repair. This treatment may also be beneficial following other types of reconstructive surgeries involving the tendon-bone interface.

Biomechanical evaluation of four different transosseous-equivalent/suture bridge rotator cuff repairs.

PURPOSE: Evaluate the biomechanical behavior of four variants of the transosseous-equivalent/suture bridge (TOE/SB) repair. METHODS: Four suture bridge (SB) constructs were created using 24 sheep infraspinatus tendon-humerus constructs (n = 6 per technique). The groups were (1) Knotted Standard Suture Bridge (Standard SB)--suture bridge with two medial mattress stitches, (2) Knotted Double Suture Bridge (Double SB)--four medial mattress stitches, (3) Untied Suture Bridge with Medial FT Anchors (Untied SB with FT)--two medial mattress stitches without knots, and (4) Untied Suture Bridge with PushLocks (Untied SB with Pushlocks)--two medial mattress stitches without knots. The contact area footprint was measured with an electronic pressure film prior to dynamic mechanical testing for gapping and testing to failure. RESULTS: The Double SB produced the greatest contact area footprint compared to the other techniques, which did not differ. The Double SB repair with a mean failure load of 456.9N was significantly stronger than the Untied SB with Pushlocks repair at 300N (P = 0.023), the standard SB repair at 295N (P = 0.019), and lastly the Untied SB with FT repair at 284N (P = 0.011). No differences were detected between the two mattress stitch standard SB repair with knots and the knotless two mattress stitch repairs (Untied SB with FT and Untied SB with Pushlocks). Gaps developed during cyclic loading in all repairs apart from the Double SB repair. CONCLUSIONS: The transosseous-equivalent/suture bridge repair with 4 stitches tied in the medial row and maximal lateral suture strand utilization (Double SB) outperformed all other repairs in terms of failure load, tendon-bone contact, and gapping characteristics. The presence of knots in the medial row did not change tendon fixation with respect to failure load, contact area or gapping characteristics.

Tratamiento artroscopico versus cirugia abierta en inestabilidad recurrente anterior de hombro: desarrollo de un meta-analisis / Arthroscopic treatment versus open surgery in previous recurrent instability of shoulder: development of a meta-analysis

Objetivo: Realizar una evaluación estadística de la literatura actual para determinar si los resultados primarios del tratamiento artroscópico superan a los resultados de la cirugía a cielo abierto considerando la patología inestabilidad anterior recurrente postraurnática de hombro. Diseño del Estudio: Meta-análisis. Métodos: Se realizó una búsqueda electrónica en la red MEDLINE de todos los estudios publicados en todos los idiomas que realizan una comparación de estas dos técnicas. Se incluyeron artículos hasta el 31 de octubre de año 2001. Se utilizaron las siguientes palabras claves: 1) anterior shoulder instability 2) Bankart lesión 3) Traumatic recurrent anterior shoulder instability y 4) arthroscopic and open bankart repair. Solo fueron incluidos aquellos artículos que efectuaron una directa comparación entre estas dos técnicas. Cada uno de estos artículos fueron manualmente revisados con el motivo de obtener artículos adicionales que no hubiesen sido detectados electrónicamente. Se evaluó estadísticamente: inestabilidad recurrente, retorno a las actividades diarias, indice de re-operación y etiología de la recurrencia. Resultados: Solo diez artículos fueron incluidos en el análisis final. Según el tipo de diseño: uno fue experimental verdadero, 2 fueron quasi-experimentales, 4 fueron estudios de cohortes y 3 estudios fueron retrospectivos. El análisis estadístico teniendo en cuenta el Pooled Mantel-Haenszel Odds Ratio para inestabilidad recurrente y para retorno al trabajo fue de 2,22 (p=0.002, 95% CI 1.36,3.65) y 2,85 (p=0.004, 95% Cl 1.40,5.78) respectivamente, a favor de la técnica realizada a cielo abierto. Conclusión: La cirugía a cielo abierto realizada por un cirujano experimentado supera a la técnica artroscópica considerando las variables inestabilidad recurrente y retorno a las actividades de la vida diaria. Nivel de Evidencia científico: Este meta-análisis combina estudios científicos nivel uno y tres ...

Tratamiento artroscopico versus cirugia abierta en inestabilidad recurrente anterior de hombro: desarrollo de un meta-analisis / Arthroscopic treatment versus open surgery in previous recurrent instability of shoulder: development of a meta-analysis

Objetivo: Realizar una evaluación estadística de la literatura actual para determinar si los resultados primarios del tratamiento artroscópico superan a los resultados de la cirugía a cielo abierto considerando la patología inestabilidad anterior recurrente postraurnática de hombro. Diseño del Estudio: Meta-análisis. Métodos: Se realizó una búsqueda electrónica en la red MEDLINE de todos los estudios publicados en todos los idiomas que realizan una comparación de estas dos técnicas. Se incluyeron artículos hasta el 31 de octubre de año 2001. Se utilizaron las siguientes palabras claves: 1) anterior shoulder instability 2) Bankart lesión 3) Traumatic recurrent anterior shoulder instability y 4) arthroscopic and open bankart repair. Solo fueron incluidos aquellos artículos que efectuaron una directa comparación entre estas dos técnicas. Cada uno de estos artículos fueron manualmente revisados con el motivo de obtener artículos adicionales que no hubiesen sido detectados electrónicamente. Se evaluó estadísticamente: inestabilidad recurrente, retorno a las actividades diarias, indice de re-operación y etiología de la recurrencia. Resultados: Solo diez artículos fueron incluidos en el análisis final. Según el tipo de diseño: uno fue experimental verdadero, 2 fueron quasi-experimentales, 4 fueron estudios de cohortes y 3 estudios fueron retrospectivos. El análisis estadístico teniendo en cuenta el Pooled Mantel-Haenszel Odds Ratio para inestabilidad recurrente y para retorno al trabajo fue de 2,22 (p=0.002, 95% CI 1.36,3.65) y 2,85 (p=0.004, 95% Cl 1.40,5.78) respectivamente, a favor de la técnica realizada a cielo abierto. Conclusión: La cirugía a cielo abierto realizada por un cirujano experimentado supera a la técnica artroscópica considerando las variables inestabilidad recurrente y retorno a las actividades de la vida diaria. Nivel de Evidencia científico: Este meta-análisis combina estudios científicos nivel uno y tres ...(AU)

Anatomic and biomechanical study of the biceps vinculum, a structure within the biceps sheath.

PURPOSE: To evaluate the anatomic, biomechanical, and histologic properties of the biceps vinculum and its potential role as a restraint to distal migration of the biceps after tenotomy. METHODS: Eight human shoulders were dissected to define the anatomic parameters of the biceps vinculum. Histologic studies were performed by sectioning through the vinculum-tendon attachment and performing H&E staining. The strength of the vinculum was tested biomechanically after sectioning the biceps origin and applying a uniaxial tension at a rate of 1 mm/s until failure. RESULTS: With regard to anatomy, the vinculum was present in all specimens, attached to the biceps tendon and proximal humerus. Excursion testing showed that the vinculum prevented the biceps origin from migrating distal to the groove entrance. The mean dimensions of the structures and excursion were as follows: biceps origin to vinculum, 43.4 mm; vinculum width on biceps side, 46.2 mm; vinculum width on bone side, 69.3 mm; length of tendon with proximal pull, 42.6 mm; and length of tendon with distal pull, 2.25 mm. With regard to histology, the membranous tissue of the biceps vinculum consisted of loose soft tissue with fat, arteries, and veins. The vinculum was seen to loosely attach to the biceps tendon and more intimately attach to the periosteal/bone side. With regard to biomechanical testing, the maximum force to failure of the vinculum was variable, ranging from 17.4 N to 227.6 N, with a mean value of 102.7 +/- 76 N. CONCLUSIONS: The biceps vinculum was a consistent membranous structure intimately associated with the biceps tendon and attached to the proximal humerus. After tenotomy at the biceps origin, the vinculum prevented distal migration of the proximal biceps tendon past the groove entrance in all specimens. Biomechanical testing showed that the vinculum provided variable resistance to distal pull. CLINICAL RELEVANCE: The properties described may help to explain why biceps tenotomy does not routinely result in a Popeye biceps deformity.

Tratamiento artroscopico versus cirugia abierta en inestabilidad recurrente anterior de hombro: desarrollo de un meta-analisis / Recurrent anterior shoulder instability: open versus arthroscopic surgery. A meta-analysis

El motivo de este analisis estadistico es hacer una evaluacion critica y de alta credibilidad cientifica de la literatura actual para determinar si los resultados primarios del tratamiento artroscopico superan a los resultados de la cirugia a cielo abierto considerando la patologia inestabilidad anterior recurrente postraumatica de hombro (resumen truncado)

Tratamiento artroscopico versus cirugia abierta en inestabilidad recurrente anterior de hombro: desarrollo de un meta-analisis / Recurrent anterior shoulder instability: open versus arthroscopic surgery. A meta-analysis

El motivo de este analisis estadistico es hacer una evaluacion critica y de alta credibilidad cientifica de la literatura actual para determinar si los resultados primarios del tratamiento artroscopico superan a los resultados de la cirugia a cielo abierto considerando la patologia inestabilidad anterior recurrente postraumatica de hombro (resumen truncado)

Arthroscopic versus open repair for traumatic anterior shoulder instability: a meta-analysis.

PURPOSE: The purpose of this study was to critically evaluate the literature to determine whether open or arthroscopic surgical repair for traumatic recurrent anterior shoulder instability results in a better outcome. TYPE OF STUDY: Meta-analysis. METHODS: The search involved clinical studies in all languages in the MEDLINE database from 1966 to October 31, 2003. The following key words were used: (1) anterior shoulder instability, (2) Bankart lesion, (3) traumatic recurrent anterior shoulder instability, and (4) arthroscopic and open Bankart repair. All abstracts were reviewed and articles were included if there was a direct clinical comparison between arthroscopic and open repair for traumatic recurrent anterior shoulder instability. These articles were manually cross-referenced for additional abstracts. The final group of articles was independently critically appraised and the following outcomes were extracted: recurrent instability, return to activity, reoperation rate, and cause of recurrence. RESULTS: The search terms resulted in 677, 183, 68, and 51 hits respectively. From these, 18 articles were determined to be eligible for full review including 2 foreign-language articles. Cross-referencing identified 2 unpublished studies. Eleven studies were included in the final analysis: 1 randomized trial, 2 pseudo-experimental designs, 4 prospective cohorts, 3 retrospective studies, and 1 case control study. Pooled Mantel-Haenszel odds ratio for recurrent instability and return to activity were 2.04 ( P = .003; 95% confidence interval, 1.27, 3.29) and 2.85 ( P = .004; 95% confidence interval, 1.40, 5.78), respectively, in favor of the open repair. CONCLUSIONS: Based on this meta-analysis, open repair has a more favorable outcome with respect to recurrence and return to activity. LEVEL OF EVIDENCE: Level III, Systematic Review of Level III (and II/I) Studies.

Should acute anterior dislocations of the shoulder be immobilized in external rotation? A cadaveric study.

The high recurrence rate associated with anterior shoulder dislocations may reflect inadequate healing of a Bankart lesion when the arm is immobilized in internal rotation. The effect of external rotation (ER) of the humerus on the glenoid-labrum contact of Bankart lesions was examined in 10 human cadaveric shoulders. The contact force between the glenoid labrum and the glenoid was measured in 60 degrees of internal rotation, neutral rotation, and 45 degrees of ER in 10 human cadaveric shoulders. No detectable contact force was found with the arm in internal rotation. The contact force increased as the arm passed through neutral rotation and reached a maximum at 45 degrees of ER. The contact force returned to 0 g when the arm was returned to neutral rotation. The mean contact force at 45 degrees of ER was 83.5 g. External rotation significantly increases the labrum-glenoid contact force and may influence the healing of a Bankart lesion.

High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence.

Akt is a serine-threonine-kinase that phosphorylates proteins in several pathways regulating aspects of metabolism, apoptosis, and proliferation. Akt signaling promotes proliferation and increased cell survival and is thought to play an important role in prostate cancer progression. Tissue microarrays (640 patients) with triplicate cores of non-neoplastic prostate, BPH, and index tumor were immunostained with antibody to Phospho-Akt (Ser473), digitized, and quantified. The expression index (Intensity*Percentage) was used for statistical analysis. P-Akt-1 staining was found in both the non-neoplastic and cancer tissues, predominantly in cytoplasmic locations. High level P-Akt-1 is expressed almost exclusively in cancer. By Kaplan-Meier actuarial model, high expression of P-Akt-1 in prostate cancer was predictive of a higher probability of recurrence on univariate and multivariate analysis. Akt-1 expression was an independent prognostic indicator of biochemical recurrence-free survival when Gleason 6 and 7 patients were analyzed separately. Surprisingly, a high level of P-Akt-1 expression in non-neoplastic tissues is also an independent predictor of biochemical recurrence. This suggests that some patients might have an inherent predisposition to express a high level of P-Akt-1 and, therefore, to have an adverse prognosis. We conclude that P-Akt-1 is most likely involved in the progression of prostate cancer and is an excellent biomarker for biochemical recurrence.

Regional antibiotic prophylaxis in elbow surgery.

In this study we describe a technique for the delivery of regional antibiotic prophylaxis in patients undergoing elbow surgery and compare tissue antibiotic concentrations achieved by this technique with those achieved by standard systemic intravenous prophylaxis. We collected bone and fat samples from patients undergoing elective elbow surgery who had received regional antibiotic prophylaxis and measured the tissue antibiotic concentration. For comparison, we measured the antibiotic concentration in bone and fat samples taken from patients undergoing elective shoulder surgery who had received systemic prophylaxis. Mean tissue antibiotic concentrations were significantly higher in the regional antibiotic group (bone, 1484 microg/g vs 35.8 microg/g; fat, 1422.7 microg/g vs 10.7 microg/g; P <.05). No adverse effects were encountered with regional antibiotic delivery. The delivery of regional antibiotic prophylaxis in elbow surgery achieves higher tissue antibiotic concentrations than those achieved with standard systemic delivery. This technique may help reduce the risk of perioperative infection in elbow surgery.

Biomechanical analysis of five fixation techniques used in glenohumeral arthrodesis.

BACKGROUND: The purpose of the present study is to compare five fixation techniques in shoulder fusion. The most common complications resulting from shoulder fusion, non-union and unacceptable arm position, might reflect a failure to achieve rigid fixation during the surgical procedure. METHODS: Twenty-five shoulder fusions were carried out on human cadaveric specimens using the following techniques: screw fixation, external fixation, external fixation supplemented with screw fixation, single plate fixation and double plate fixation. Each specimen was tested on a servohydraulic machine to determine stiffness. RESULTS: There was a statistically significant difference in bending and torsional stiffness between all five fixation techniques. Normalized bending (B) and torsional stiffness (T), in descending order, were: double plate (B = 1.00, T = 1.00), single plate (B = 0.77, T = 0.89), external fixation with screws (B = 0.68, T = 0.74), external fixation alone (B = 0.40, T = 0.53), and screws alone (B = 0.13, T = 0.26). CONCLUSION: The risk of the most common complications resulting from shoulder fusion might be minimized if these biomechanical findings are applied to surgical decision making.