Outcome of Reverse Shoulder Arthroplasty for Patients With Parkinson's Disease: A Matched Cohort Study.

Parkinson's disease (PD) is a progressive neurologic disorder that affects the musculoskeletal system. Currently, the use of reverse shoulder arthroplasty (RSA) for patients with PD has not been adequately studied. The authors sought to determine if RSA provided similar functional outcomes for patients with PD compared with a matched cohort of patients without PD. Between 2004 and 2011, 10 patients with PD (4 men, 6 women) underwent RSA. Patients with PD were matched to patients without PD at a 1:4 ratio based on age (average, 76 years; range, 63-85 years), sex (16 men, 24 women), preoperative diagnosis, and length of follow-up (average, 43 months; range, 24-128 months). Outcome measures included range of motion, visual analog scale (VAS) score, Simple Shoulder Test (SST) score, American Shoulder and Elbow Society (ASES) score, and complication rates. Patients with PD had improvements in SST scores, ASES total scores, and forward flexion; however, they did not show statistically significant improvements in VAS scores, ASES function scores, or other range of motion parameters. There was a significant difference in postoperative functional outcome scores, SST scores, and internal/external rotation between the 2 groups, but no difference in postoperative pain scores, ASES total scores, forward flexion, or abduction. Complications occurred in 4 of 10 patients with PD and 6 of 40 patients without PD. Compared with the matched cohort, patients with PD achieved similar reduction of pain but inferior clinical function following RSA. Improvement in range of motion was less predictable and complication rates were significantly higher in patients with PD. [Orthopedics. 2017; 40(4):e675-e680.].

An inter-species protein-protein interaction network across vast evolutionary distance.

In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional network coordination is shaped by evolutionary forces are all largely unanswered questions. Here, we investigate these questions using an "inter-interactome" approach. We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network. After a billion years of evolutionary divergence, the yeast and human proteomes are still capable of forming a biophysical network with properties that resemble those of intra-species networks. Although substantially reduced relative to intra-species networks, the levels of functional overlap in the yeast-human inter-interactome network uncover significant remnants of co-functionality widely preserved in the two proteomes beyond human-yeast homologs. Our data support evolutionary selection against biophysical interactions between proteins with little or no co-functionality. Such non-functional interactions, however, represent a reservoir from which nascent functional interactions may arise.

Reverse shoulder arthroplasty for massive rotator cuff tear: risk factors for poor functional improvement.

BACKGROUND: Some patients unexpectedly have poor functional improvement after reverse shoulder arthroplasty (RSA) for massive rotator cuff tear without glenohumeral arthritis. Our aim was to identify risk factors for this outcome. We also assessed the value of RSA for cases with poor functional improvement vs. METHODS: The study was a retrospective case-control analysis for primary RSA performed for massive rotator cuff tear without glenohumeral arthritis with minimum 2-year follow-up. Cases were defined as Simple Shoulder Test (SST) score improvement of ≤1, whereas controls improved SST score ≥2. Risk factors were chosen on the basis of previous association with poor outcomes after shoulder arthroplasty. Latissimus dorsi tendon transfer results were analyzed as a subgroup. Value was defined as improvement in American Shoulder and Elbow Surgeons (ASES) score per $10,000 hospital cost. RESULTS: In a multivariate binomial logistic regression analysis, neurologic dysfunction (P = .006), age <60 years (P = .02), and high preoperative SST score (P = .03) were independently associated with poor functional improvement. Latissimus dorsi tendon transfer patients significantly improved in active external rotation (-0.3° to 38.7°; P < .01). The value of RSA (ΔASES/$10,000 cost) for cases was 0.8 compared with 17.5 for controls (P < .0001). CONCLUSIONS: Young age, high preoperative function, and neurologic dysfunction were associated with poor functional improvement. Surgeons should consider these associations in counseling and selection of patients. Concurrent latissimus dorsi transfer was successful in restoring active external rotation in a subgroup of patients. The critical economic importance of improved patient selection is emphasized by the very low value of the procedure in the case group.

Widespread macromolecular interaction perturbations in human genetic disorders.

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

Complex trauma to the shoulder girdle, including the proximal humerus, the clavicle, and the scapula: current concepts in diagnosis and treatment.

Fractures to the shoulder girdle are common injuries in an aging population. Many techniques and theories lie behind the treatment of such injuries. Knowledge and understanding of current concepts for diagnosing and treating proximal humeral, clavicular, and scapular fractures and the theory behind them will help surgeons make informed decisions with regard to patient care.

Outcome and value of reverse shoulder arthroplasty for treatment of glenohumeral osteoarthritis: a matched cohort.

BACKGROUND: Total shoulder arthroplasty (TSA) is commonly used to treat glenohumeral osteoarthritis (GHOA) with an intact rotator cuff. Recently, reverse shoulder arthroplasty (RSA) has been used for GHOA patients who are elderly or have eccentric glenoid wear. We evaluated patients with GHOA scheduled to have TSA but who were changed to RSA because of intraoperative difficulties with the glenoid component or instability and compared them with a cohort that underwent TSA to determine if the groups had similar outcomes. METHODS: We identified 24 consecutive GHOA patients who underwent RSA and matched them to 96 patients who underwent TSA. Glenoid wear and rotator cuff musculature were assessed with preoperative computed tomography scans. Direct hospital costs of the procedure were collected. RESULTS: Postoperative American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, and range of motion were similar between the 2 groups. Five TSA patients had radiographic glenoid loosening, whereas no RSA patients did. Neither group required a revision. One RSA patient required surgery for treatment of a periprosthetic fracture. RSA was $7274 more costly than TSA, related mainly to implant cost. CONCLUSIONS: Patients with GHOA who were converted intraoperatively to RSA because of improper seating of the glenoid trial or persistent posterior subluxation had outcomes comparable to those of a similar group of patients in whom TSA was performed. At midterm follow-up, TSA is associated with lower cost than RSA. The higher rate of radiographic loosening in the TSA group warrants longer follow-up to assess revision costs. In cases in which a TSA cannot be performed with confidence, RSA is a reasonable alternative.

Glenosphere dissociation after reverse shoulder arthroplasty.

BACKGROUND: Reverse shoulder arthroplasty (RSA) is gaining popularity for the treatment of debilitating shoulder disorders. Despite marked improvements in patient satisfaction and function, the RSA complication rate is high. Glenosphere dissociation has been reported and may result from multiple mechanisms. However, few RSA retrieval studies exist. METHODS: We reviewed our RSA database and identified patients with glenosphere dissociation between 1999 and 2013. Prosthesis type, glenosphere size, and contributing factors to dissociation were noted. Five retrieved implants were available for analysis, and evidence of wear or corrosion on the Morse taper was documented. Further, we biomechanically investigated improper Morse taper engagement that may occur intraoperatively as a potential cause of acute dissociation. RESULTS: Thirteen patients with glenosphere dissociation were identified (0.5 months to 7 years postoperatively). Glenosphere size distribution was as follows: 32 mm (n = 1), 36 mm (n = 4), 40 mm (n = 6), and 44 mm (n = 2). Incidence of dissociation was correlated to glenosphere size (P < .001). Taper damage was limited to fretting wear, and there was minimal evidence of taper corrosion. Biomechanically, improper taper engagement reduced the torsional capacity of the glenosphere-baseplate interface by 60% from 19.2 ± 1.0 N-m to 7.5 ± 1.5 N-m. CONCLUSION: We identified several mechanisms contributing to glenosphere dissociation after RSA, including trauma and improper taper engagement. Limited evidence of corrosive wear on the taper interface was identified. Although it is rare, the incidence of glenosphere dissociation was higher when 40- and 44-mm glenospheres were implanted compared with smaller glenospheres (32 and 36 mm), probably because of the larger exposed surface area for potential impingement.

The effects of glenoid wear patterns on patients with osteoarthritis in total shoulder arthroplasty: an assessment of outcomes and value.

BACKGROUND: Despite the success of total shoulder arthroplasty (TSA), concerns remain about the longevity of the implant, in particular, glenoid component survivorship. The purpose of this study was to determine whether preoperative glenoid wear patterns affect clinical outcomes and value in patients undergoing TSA. METHODS: A comparative cohort study was conducted of 309 patients with a total of 344 TSA procedures, performed for primary glenohumeral osteoarthritis. Computed tomography scans were obtained in all patients, with preoperative glenoid wear pattern characterized as either concentric (n = 196; follow-up time, 49.2 months) or eccentric (n = 148; follow-up time, 52.3 months) according to a modified Levine classification. A clinical, radiographic, and economic assessment was performed between the 2 wear patterns. RESULTS: There was no significant difference in American Shoulder and Elbow Surgeons (ASES) score in the concentric group (80.8 ± 20.8) compared with the eccentric group (77.6 ± 21.2) at final follow-up (P = .159). Range of motion and final visual analog scale for pain score were similar between the 2 groups. Radiographic evidence of gross glenoid loosening was significantly lower in the concentric group [11 of 195 (5.6%)] compared with the eccentric group [18 of 147 (12.2%)] (P = .030). Revision rates were similar between the concentric group [4 of 195 (2.0%)] and the eccentric group [3 of 147 (2.0%)]. A value assessment also showed no significant difference between the concentric and eccentric groups [concentric 26.1 vs. eccentric 25.5 (ΔASES score/$10,000 hospital cost) (P = .479)]. CONCLUSIONS: Similar clinical results and value can be expected with both concentric and eccentric glenoid wear patterns in TSA. Concerns arise, however, as the eccentric group demonstrated a more than 2-fold increased rate of glenoid component loosening compared with the concentric group.

Low incidence of tendon rerupture after distal biceps repair by cortical button and interference screw.

BACKGROUND: The use of cortical suspensory fixation in conjunction with an interference screw to treat distal biceps ruptures has yielded favorable results. However, literature examining the incidence of fixation failure in a large consecutive series of patients treated with this technique is lacking. METHODS: A retrospective review of electronic medical records identified 170 distal biceps ruptures in 168 consecutive patients (164 men and 4 women) treated using a cortical button in conjunction with an interference screw. The study group was an average age of 48 years (range, 20-71 years). Records were reviewed from the time of the initial clinic visit to the most recent follow-up. Early failures were defined as those that occurred within 12 weeks of the index procedure. Failed repair was defined as tendon defect, deformity, or significant weakness in supination. RESULTS: The early incidence of failure was 1.2%, with 2 of the fixations meeting the criteria for failure. One patient had significant brachial artery thrombosis. Other complications included posterior interosseous nerve palsy, lateral antebrachial cutaneous nerve-related complication, and numbness about the radial nerve. CONCLUSION: The use of a cortical suspensory fixation device in conjunction with an interference screw is an effective method of repairing a distal biceps rupture, with a low early rate of failure.

Accuracy and reliability of the Mayo Elbow Performance Score.

PURPOSE: To test the reliability of the Mayo Elbow Performance Score (MEPS) and compare it with a validated outcomes instrument, the American Shoulder and Elbow Surgeons (ASES) score. METHODS: A total of 42 patients with the chief problem of elbow dysfunction formed the study cohort. Patients with an immediate surgical indication or treatment at the index visit were excluded. The others completed an MEPS questionnaire; at a second visit 2 to 3 weeks later, they completed another MEPS questionnaire and were evaluated with the ASES elbow assessment. Reliability and accuracy were calculated using 2-tailed Pearson correlation coefficients with 95% confidence intervals. Pearson coefficients greater than 0.8 indicated strong agreement. RESULTS: The average MEPS score at the initial visit was 58. At the second visit, the average MEPS score was 69 and the average ASES score was 78. The Pearson coefficient for MEPS scores at the 2 time points averaged 0.82, and between the MEPS and ASES scores averaged 0.83. Both coefficients indicated strong agreement. CONCLUSIONS: The MEPS has strong reliability when assessed at different times and when compared with a validated elbow outcomes instrument. Differences in compared scores of approximately 10 points indicate some patient improvement between time points; however, 95% confidence intervals, standard deviations, and ranges were essentially equivalent between and among tests, indicating similar accuracy. CLINICAL RELEVANCE: The MEPS is a reliable outcomes instrument for clinical studies of elbow function that is used to assess nonsurgical treatment.

Edgotype: a fundamental link between genotype and phenotype.

Classical 'one-gene/one-disease' models cannot fully reconcile with the increasingly appreciated prevalence of complicated genotype-to-phenotype associations in human disease. Genes and gene products function not in isolation but as components of intricate networks of macromolecules (DNA, RNA, or proteins) and metabolites linked through biochemical or physical interactions, represented in 'interactome' network models as 'nodes' and 'edges', respectively. Accordingly, mechanistic understanding of human disease will require understanding of how disease-causing mutations affect systems or interactome properties. The study of 'edgetics' uncovers specific loss or gain of interactions (edges) to interpret genotype-to-phenotype relationships. We review how distinct genetic variants, the genotype, lead to distinct phenotypic outcomes, the phenotype, through edgetic perturbations in interactome networks altogether representing the 'edgotype'.

SD-OCT and autofluorescence characteristics of autoimmune retinopathy.

AIMS: To report abnormal fundus hyperautofluorescence (hyper-AF) and loss of outer retinal layers by spectral domain optical coherence tomography in patients with autoimmune retinopathy (AIR). METHODS: Retrospective, observational case series of 14 eyes of 7 patients diagnosed with an AIR for whom colour fundus photographs, fundus AF images and spectral domain optical coherence tomograms (SD-OCT) were obtained at presentation. RESULTS: Seven patients were identified ranging in age from 24 to 73 years. Six had a history of cancer and were diagnosed with cancer associated retinopathy or melanoma associated retinopathy. Among the seven patients, six (86%) had abnormalities by AF or SD-OCT including loss of outer retinal layers in association with hyper-AF. One patient with melanoma associated retinopathy did not have any imaging abnormalities. In one patient with cancer associated retinopathy followed over 8 months, progressive loss of retinal architecture was associated with the formation of a hyper-AF ring. CONCLUSIONS: Patients with AIR can present with structural abnormalities that are detectable by fundus AF and SD-OCT. The areas of hyper-AF correspond to loss of outer-retinal structures such as the inner segment/outer segment junction, the external limiting membrane and outer nuclear layer. These imaging modalities may be useful in establishing the diagnosis of this rare disease, monitoring disease progression and evaluating response to therapy.

Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor.

The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT.

Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.

Viral perturbations of host networks reflect disease etiology.

Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.

Proto-genes and de novo gene birth.

Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or 'non-genic' sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions. Here we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes generated by widespread translational activity in non-genic sequences. Testing this model at the genome scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events seem to provide adaptive potential, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation.

Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) and type 2 both target T lymphocytes, yet induce radically different phenotypic outcomes. HTLV-1 is a causative agent of Adult T-cell leukemia (ATL), whereas HTLV-2, highly similar to HTLV-1, causes no known overt disease. HTLV gene products are engaged in a dynamic struggle of activating and antagonistic interactions with host cells. Investigations focused on one or a few genes have identified several human factors interacting with HTLV viral proteins. Most of the available interaction data concern the highly investigated HTLV-1 Tax protein. Identifying shared and distinct host-pathogen protein interaction profiles for these two viruses would enlighten how they exploit distinctive or common strategies to subvert cellular pathways toward disease progression. RESULTS: We employ a scalable methodology for the systematic mapping and comparison of pathogen-host protein interactions that includes stringent yeast two-hybrid screening and systematic retest, as well as two independent validations through an additional protein interaction detection method and a functional transactivation assay. The final data set contained 166 interactions between 10 viral proteins and 122 human proteins. Among the 166 interactions identified, 87 and 79 involved HTLV-1 and HTLV-2 -encoded proteins, respectively. Targets for HTLV-1 and HTLV-2 proteins implicate a diverse set of cellular processes including the ubiquitin-proteasome system, the apoptosis, different cancer pathways and the Notch signaling pathway. CONCLUSIONS: This study constitutes a first pass, with homogeneous data, at comparative analysis of host targets for HTLV-1 and -2 retroviruses, complements currently existing data for formulation of systems biology models of retroviral induced diseases and presents new insights on biological pathways involved in retroviral infection.

Protein-protein interactions and networks: forward and reverse edgetics.

Phenotypic variations of an organism may arise from alterations of cellular networks, ranging from the complete loss of a gene product to the specific perturbation of a single molecular interaction. In interactome networks that are modeled as nodes (macromolecules) connected by edges (interactions), these alterations can be thought of as node removal and edge-specific or "edgetic" perturbations, respectively. Here we present two complementary strategies, forward and reverse edgetics, to investigate the phenotypic outcomes of edgetic perturbations of binary protein-protein interaction networks. Both approaches are based on the yeast two-hybrid system (Y2H). The first allows the determination of the interaction profile of proteins encoded by alleles with known phenotypes to identify edgetic alleles. The second is used to directly isolate edgetic alleles for subsequent in vivo characterization.

Next-generation sequencing to generate interactome datasets.

Next-generation sequencing has not been applied to protein-protein interactome network mapping so far because the association between the members of each interacting pair would not be maintained in en masse sequencing. We describe a massively parallel interactome-mapping pipeline, Stitch-seq, that combines PCR stitching with next-generation sequencing and used it to generate a new human interactome dataset. Stitch-seq is applicable to various interaction assays and should help expand interactome network mapping.

Interactome networks and human disease.

Complex biological systems and cellular networks may underlie most genotype to phenotype relationships. Here, we review basic concepts in network biology, discussing different types of interactome networks and the insights that can come from analyzing them. We elaborate on why interactome networks are important to consider in biology, how they can be mapped and integrated with each other, what global properties are starting to emerge from interactome network models, and how these properties may relate to human disease.