Cemented humeral stem versus press-fit humeral stem in total shoulder arthroplasty: a systematic review and meta-analysis.

AIMS: The aim of this study was to evaluate the differences in revision and complication rates, functional outcomes, and radiological outcomes between cemented and press-fit humeral stems in primary anatomical total shoulder arthroplasty (TSA). MATERIALS AND METHODS: A comprehensive systematic review and meta-analysis was conducted searching for studies that included patients who underwent primary anatomical TSA for primary osteoarthritis or rheumatoid arthritis. RESULTS: There was a total of 36 studies with 927 cemented humeral stems and 1555 press-fit stems. The revision rate was 5.4% (95% confidence interval (CI) 3.9 to 7.4) at a mean of 89 months for cemented stems, and 2.4% (95% CI 1.1 to 4.7) at a mean of 40 months for press-fit stems. A priori subgroup analysis to control for follow-up periods demonstrated similar revision rates: 2.3% (95% CI 1.1 to 4.7) for cemented stems versus 1.8% (95% CI 1.4 to 2.9) for press-fit stems. Exploratory meta-regression found that longer follow-up was a moderating variable for revision (p = 0.003). CONCLUSION: Cement fixation had similar revision rates when compared to press-fit stems at short- to midterm follow-up. Rotator cuff pathology was a prevalent complication in both groups but is likely not related to fixation type. Overall, with comparable revision rates, possible easier revision, and decreased operative time, humeral press-fit fixation may be an optimal choice for primary anatomical TSA in patients with sufficient bone stock. Cite this article: Bone Joint J 2019;101-B:1107-1114.

Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.

BACKGROUND: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. PATIENTS AND METHODS: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. RESULTS: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. CONCLUSIONS: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Acute mobilization and migration of bone marrow-derived stem cells following anterior cruciate ligament rupture.

OBJECTIVE: Little is known regarding acute local and systemic processes following anterior cruciate ligament (ACL) rupture. No study has elucidated whether bone marrow-derived mesenchymal stem cells (MSCs) are mobilized into circulation and recruited to the injured joint. METHODS: In Part 1, Lewis rats were randomized to noninvasive ACL rupture (Rupture) or non-injured (Control) (n = 6/group). After 72 h, whole blood MSC concentration was assessed using flow cytometry. Synovial fluid and serum were assayed for stromal cell-derived factor (SDF)-1α and cartilage degeneration biomarkers, respectively. In Part 2, 12 additional rats were randomized and intravenously-injected with fluorescently-labeled allogenic MSCs. Cell tracking was performed using longitudinal, in vivo and ex vivo near-infrared (NIR) imaging and histology. Synovium SDF-1α and interleukin (IL)-17A immunostaining was performed. Serum was assayed for SDF-1α and 29 other cytokines. RESULTS: In Part 1, there was a significant increase in MSC concentration and synovial fluid SDF-1α in Rupture. No differences in cartilage biomarkers were observed. In Part 2, Rupture had significantly higher NIR signal at 24, 48, and 72 h, indicating active recruitment of MSCs to the injured joint. Ex vivo cell tracking demonstrated MSC localization in the synovium and myotendinous junction (MTJ) of the quadriceps. Injured synovia exhibited increased synovitis grade and higher degree of IL-17A and SDF-1α immunostaining. CONCLUSION: ACL rupture induced peripheral blood mobilization of MSCs and migration of intravenously-injected allogenic MSCs to the injured joint, where they localized in the synovium and quadriceps MTJ.

Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear.

OBJECTIVES: Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. METHODS: Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. RESULTS: At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. CONCLUSIONS: GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred.Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57-65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1.

Patient-derived xenografts as tools in pharmaceutical development.

Successful drug development in oncology is grossly suboptimal, manifested by the very low percentage of new agents being developed that ultimately succeed in clinical approval. This poor success is in part due to the inability of standard cell-line xenograft models to accurately predict clinical success and to tailor chemotherapy specifically to a group of patients more likely to benefit from the therapy. Patient-derived xenografts (PDXs) maintain the histopathological architecture and molecular features of human tumors, and offer a potential solution to maximize drug development success and ultimately generate better outcomes for patients. Although imperfect in mimicking all aspects of human cancer, PDXs are a more predictable platform for preclinical evaluation of treatment effect and in selected cases can guide therapeutic decision making in the clinic. This article summarizes the current status of PDX models, challenges associated with modeling human cancer, and various approaches that have been applied to overcome these challenges and improve the clinical relevance of PDX cancer models.

T lymphocytes are not required for the development of fatty degeneration after rotator cuff tear.

OBJECTIVES: Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as 'fatty degeneration'. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified. METHODS: A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation. RESULTS: Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present. CONCLUSIONS: The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles. Cite this article: Bone Joint Res 2014;3:262-72.

Radiographic prevalence of CAM-type femoroacetabular impingement after open reduction and internal fixation of femoral neck fractures.

PURPOSE: The purpose of this study was to estimate the radiographic prevalence of CAM-type femoroacetabular impingement (FAI) in elderly patients (≥ 50 years) who have undergone internal fixation for femoral neck fracture. METHODS: A total of 187 frog-leg lateral radiographs of elderly patients who underwent internal fixation for a femoral neck fracture were reviewed by two independent reviewers. The alpha angle, beta angle, and femoral head-neck offset ratio were calculated. The presence of two abnormal radiographic parameters was deemed to be diagnostic of radiographic CAM-type impingement. RESULTS: Radiographic CAM-type FAI was identified in 157 out of 187 (84 %) patients who underwent internal fixation for fractures of the femoral neck. Moderate-to-good inter-observer reliability was achieved in the measurement of radiographic parameters. With reference to fracture subtypes and prevalence of radiographic features of CAM-type morphology, 97 (72 %) out of 134 patients were positive for CAM in Garden subtypes I and II, whereas 49 (85.9 %) out of 57 patients had radiographic CAM in Garden III and IV subtypes. CONCLUSION: There was a high prevalence of CAM-type FAI in patients that underwent surgical fixation of femoral neck fractures. This is significantly higher than the reported prevalence in non-fracture patient populations. The high prevalence of CAM morphology could be related to several factors, including age, fracture morphology, quality of reduction, type of fixation, and fracture healing.

Arthroscopic hip preservation surgery: current concepts and perspective.

The technical advances in arthroscopic surgery of the hip, including the improved ability to manage the capsule and gain extensile exposure, have been paralleled by a growth in the number of conditions that can be addressed. This expanding list includes symptomatic labral tears, chondral lesions, injuries of the ligamentum teres, femoroacetabular impingement (FAI), capsular laxity and instability, and various extra-articular disorders, including snapping hip syndromes. With a careful diagnostic evaluation and technical execution of well-indicated procedures, arthroscopic surgery of the hip can achieve successful clinical outcomes, with predictable improvements in function and pre-injury levels of physical activity for many patients.This paper reviews the current position in relation to the use of arthroscopy in the treatment of disorders of the hip.

What does it take to have a high-grade pivot shift?

UNLABELLED: The pivot shift is the most specific clinical test to assess pathological knee joint rotatory laxity following ACL injury. This article attempts to describe the anatomic structures responsible for creating a high-grade pivot shift and their potential role in customizing ACL reconstruction. A review of the literature demonstrates that disruption of the secondary stabilizers of anterior translation of the lateral compartment including the lateral meniscus, anterolateral capsule, and IT band contributes to a high-grade pivot shift in the ACL-deficient knee. The morphology of the lateral tibial plateau, including increased posteroinferior tibial slope and small size, can also contribute to high-grade pivot shift. Factors that may decrease the grade of the pivot shift include medial compartment injury, MCL injury, patient guarding, and osteoarthritis. In conclusion, a high-grade pivot shift in the ACL-deficient knee is often associated with incompetence of the lateral soft tissue envelope. Rotatory laxity as assessed by the pivot shift may also be falsely underestimated by concomitant injuries. LEVEL OF EVIDENCE: IV.

Irreducible rectal prolapse: emergency surgical management of eight cases and a review of the literature.

The management of irreducible rectal prolapse is controversial. Surgeons may attempt conservative management by application of sugar. When surgery becomes inevitable the choice of procedure varies. We reviewed eight cases and noted the clinical findings and the results of conservative and surgical management. In four cases sugar was applied first, and failed. Emergency surgery always gave good outcomes. The procedures included simple reduction, rectopexy, laparotomy with resection, Delorme's repair, and perineal resection. Our experience and review of the literature indicate that surgery should be performed early in irreducible prolapse. Perineal resection may be the most suitable emergency procedure.

Xenon has no effect on cytokine balance and adhesion molecule expression within an isolated cardiopulmonary bypass system.

BACKGROUND: Although almost inert chemically, xenon is not unreactive biologically. It interacts with receptors involved in the expression of cytokines and adhesion molecules. The effect of xenon on the immune function in whole blood has not been studied. METHODS: We examined the effects of 70% xenon in oxygen on cytokine balance and expression of adhesion molecules in an isolated cardiopulmonary bypass (CPB) system, which simulates an evolving inflammatory response. Whole blood from 10 healthy male volunteers was circulated in a CBP system supplied with either 70% xenon in oxygen, or oxygen-enriched air - FO(2)=0.3 (control). We took samples of blood after 30, 60 and 90 min of simulated CBP. We measured interleukin (IL)-1beta, tumour necrosis factor (TNF)alpha, IL-8, IL-10, IL-1ra and TNF-sr-2 levels, and the expression of HLA-DR and the adhesion molecules L-selectin, CD18 and CD11b on monocytes, granulocytes and lymphocytes. RESULTS: IL-8 concentrations were increased significantly, TNF-sr-2 concentrations decreased significantly and IL-10 levels decreased during bypass. There were no significant differences between the groups for any measured variable. CONCLUSION: In an isolated CPB system, xenon and oxygen-enriched air had similar effects on cytokine production and expression of adhesion molecules.

The effects of subanaesthetic concentrations of xenon in volunteers.

This study reports the subjective, psychomotor and physiological properties of subanaesthetic concentrations of xenon. Ten healthy male volunteers received either xenon or nitrous oxide in a randomised crossover study design. The subjects breathed either xenon (Xe) or nitrous oxide (N2O) from a closed circuit breathing system, according to a randomised, double-blind protocol. The concentration of xenon required to produce sedation, ranged between 27 and 45% (median 35%). All subjects completed the xenon protocol. Subjects were tested using the Critical Flicker Fusion test and derived electroencephalogram parameters, however, neither test was found to reliably predict sedation. The respiratory rate decreased markedly during sedation with xenon. The subjects did not experience any airway irritability (coughing, breath-holding or laryngospasm) during administration of either gas. One subject required anti-emetic treatment in the N2O group compared to none in the Xe group. Eight subjects reported that they found sedation with xenon pleasant and preferable to nitrous oxide. Xenon sedation was well tolerated and was not associated with any adverse physiological effects, however, it was reported to be subjectively dissimilar to nitrous oxide.

'The metabolism of tumours': 70 years later.

Otto Warburg's classic treatise on the reprogramming of tumour metabolism from oxidative to glycolytic metabolism was published in London in 1930. Although the Warburg effect is one of the most universal characteristics of solid tumours, the molecular basis for this phenomenon has only recently been elucidated by studies indicating that increased expression of genes encoding glucose transporters and glycolytic enzymes in tumour cells is mediated by the transcription factors c-MYC and HIF-1. Whereas c-myc is a direct target for oncogenic mutations, expression of hypoxia-inducible factor 1 (HIF-1) is indirectly up-regulated via gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes that result increased HIF-1alpha protein expression and/or increased HIF-1 transcriptional activity in a cell-type-specific manner. As a result of genetic alterations and intratumoral hypoxia, HIF-1alpha is overexpressed in the majority of common human cancers relative to the surrounding normal tissue. In human breast cancer and brain tumours, HIF-1alpha overexpression is strongly correlated with tumour grade and vascularity.

Prolonged QRS duration (QRS >/=170 ms) and left axis deviation in the presence of left bundle branch block: A marker of poor left ventricular systolic function?

BACKGROUND: Left bundle branch block (LBBB) is commonly associated with structural heart disease and left ventricular dysfunction. We propose that the QRS duration and degree of left-axis deviation (LAD) identify significant left ventricular systolic dysfunction in patients with LBBB. METHODS: In this prospective study the ejection fraction (EF) of 300 consecutive patients with LBBB was evaluated by echocardiography. The relationship between QRS duration and LAD (axis between -30 degrees and -90 degrees ) and EF were derived. RESULTS: There was no significant difference in age, sex, presence of ischemic or nonischemic cardiomyopathy and valvular heart disease, and EF among the patients with or without LAD. The EF of patients with QRS >/=170 milliseconds with LAD (n = 20) and without LAD (n = 18) was 25% +/- 16% and 23% +/- 13%, respectively (P =.71). The mean EF (24% +/- 10%) of the patients with a QRS duration of >/=170 milliseconds (n = 38) was significantly lower than the mean EF (36% +/- 16%) of the patients with a QRS duration of <170 milliseconds (n = 262, P <.015). The QRS duration also had a significant (P <.001) inverse correlation with EF (R = 0.37, adjusted R (2) = 0.13, SE of estimate = 16.21). However, the QRS axis was not significantly correlated with EF and did not have added predictive value. CONCLUSIONS: The QRS duration has a significant inverse relationship with EF and prolongation of QRS duration (>/=170 milliseconds) in the presence of LBBB is a marker of significant left ventricular systolic dysfunction. The presence of LAD in LBBB does not signify a further decrease in EF.

Acute renal infarction secondary to left ventricular thrombus, masquerading as a renal calculus--a case report and brief review of literature.

Acute embolic renal infarction is an entity that is often misdiagnosed as a renal calculus because of similar presenting symptoms. This leads to delay in the initiation of treatment and to increased morbidity. Few case reports exist relating cardiac emboli to acute renal infarction. The authors present a patient with a renal embolism secondary to left ventricular thrombus. A brief review of the literature highlighting the importance of clinical suspicion in making an accurate diagnosis, the utility of various diagnostic studies, and comparison of various treatment options is presented.

The in vitro performance of carbon dioxide absorbents with and without strong alkali apparatus.

We report the in vitro longevity of a conventional soda lime carbon dioxide absorbent and an absorbent free from strong alkali (Amsorb). Although the times taken to breakthrough of carbon dioxide (> 0.5%) within an in vitro low flow breathing system were shorter with the alkali-free absorbent, we found that the size and shape of the absorbent container was the major factor in determining the efficiency of the carbon dioxide absorbents.

Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB.

TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IkappaBalpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.