Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis.

Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.

Mechanical Complications of Hip and Knee Spacers Are Common.

Introduction Two-stage revision is frequently used for the treatment of periprosthetic joint infection (PJI). Because antibiotic-loaded cement spacers are constructed and implanted as temporary devices, mechanical complications are possible. The purpose of our study was to define the incidence of such mechanical complications, determine associated risk factors, and establish if such complications influence the subsequent success of PJI treatment. Methods We identified patients who received an antibiotic spacer for the treatment of PJI at a single center over a six-year timeframe. Medical records and all radiographs were collected and reviewed. Radiographic changes over time were recorded, and mechanical complications were noted. We used multivariate logistic regression analysis to assess risk factors for mechanical spacer complications and assess whether such complications influence the likelihood of subsequent reimplantation and ultimate component retention. Results A total of 236 patients were included in the study. There were 82 hip spacers (28% dynamic and 72% static) with a mechanical complication rate of 8.5% and 154 knee spacers (44% dynamic and 56% static) with a mechanical complication rate of 18.2%. Knee spacers were significantly more likely to have mechanical complications than hip spacers. Other risk factors for mechanical complications included bone loss and elevated body mass index (BMI). Bone loss and advanced age were found to be independent risk factors for failure to undergo second-stage reimplantation. Mechanical spacer failure was not an independent risk factor for the likelihood of subsequent reimplantation or ultimate component retention. Conclusions Mechanical complications of antibiotic spacers are common but do not appear to negatively impact the likelihood of subsequent reimplantation or component retention. In knee spacers and in patients with bone loss or elevated BMI, appropriate patient counseling and strategies to prevent such complications are recommended.

Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons.

The lateral hypothalamic area (LHA) coordinates an array of fundamental behaviors, including sleeping, waking, feeding, stress and motivated behavior. The wide spectrum of functions ascribed to the LHA may be explained by a heterogeneous population of neurons, the full diversity of which is poorly understood. We employed a droplet-based single-cell RNA-sequencing approach to develop a comprehensive census of molecularly distinct cell types in the mouse LHA. Neuronal populations were classified based on fast neurotransmitter phenotype and expression of neuropeptides, transcription factors and synaptic proteins, among other gene categories. We define 15 distinct populations of glutamatergic neurons and 15 of GABAergic neurons, including known and novel cell types. We further characterize a novel population of somatostatin-expressing neurons through anatomical and behavioral approaches, identifying a role for these neurons in specific forms of innate locomotor behavior. This study lays the groundwork for better understanding the circuit-level underpinnings of LHA function.

Reduction Loss After Distal Radius Fracture Fixation With Locked Volar Plates.

Distal radius fractures are among the most common injuries in the upper extremity. While many studies have looked at the maintenance of reduction with volar locking plates, there is a paucity of literature comparing the ability of different plates to maintain reduction over time. This study reviews the ability of various plates to maintain radiographic reduction at union after distal radius fracture treatment. Loss of some aspect of fracture reduction was routinely observed following locked volar plating regardless of implant. However, choice of implant did have a significant impact on final radiographic alignment, particularly with respect to volar tilt and ulnar variance. Yet, selecting between a fixed angle versus a variable angle was not found to make a difference in maintaining reduction. The authors recommend that surgeons take these findings into consideration when selecting a volar locking plate. (Journal of Surgical Orthopaedic Advances.

The Efficacy of Platelet-Rich Plasma for Incision Healing After Total Ankle Replacement Using the Agility Total Ankle Replacement System.

BACKGROUND: The use of platelet-rich plasma (PRP) to aid in healing of operative incisions has been well documented in the literature. Most studies have been conducted retrospectively with small sample sizes and are conflicting in their outcomes. As such, no consensus exists regarding the utility of PRP for augmenting incisional healing. The Agility total ankle replacement (TAR) poses a significant challenge with respect to incisional healing in the immediate postoperative time frame and was used as a standardized implant in this study. We hypothesized that treating the anterior incision with PRP after Agility TAR would reduce the incidence of incision healing complications. METHODS: A retrospective review of 133 consecutive Agility TAR performed by a single surgeon at a single institution was conducted. Platelet-rich plasma was used to augment incisional closure in 78 patients undergoing TAR. Fifty-five patients had incisional closure without PRP application. Incision healing complications were stratified into patients healing without any complications (none), patients requiring prolonged local wound care (minor), and patients requiring a return to the operation theater to address an incisional complication (major). RESULTS: No statistically significant difference existed between patients treated with PRP incisional augmentation and those without PRP augmentation. Eight patients (10.3%) receiving PRP underwent operative treatment of an incisional complication, whereas 3 patients (5.5%) who had a nonaugmented closure required operative treatment (P = .52). The incidence of minor complications was not statistically significant, with 25 (32.1%) patients receiving PRP and 15 (27.3) patients who had a nonaugmented closure requiring prolonged local treatment (P = .85). CONCLUSIONS: Limited data exist regarding the use of PRP in the augmentation of the closure of operative incisions. We were unable to find a statistically significant reduction in incision-related complications in patients who had their incisions augmented with PRP. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Patellar clunk syndrome after total knee arthroplasty; risk factors and functional outcomes of arthroscopic treatment.

This study reports the incidence, risk factors, and functional outcomes of the largest reported series of patients treated arthroscopically for patella clunk syndrome (PCS). All patients treated arthroscopically for PCS were identified. Patients were matched with controls by sex and date of surgery. Follow-up was conducted using SF-12 and WOMAC questionnaires. Operative notes and preoperative and postoperative radiographs were reviewed. Seventy-five knees in 68 patients were treated arthroscopically for PCS. Average follow-up was 4.2 years. Functional scores demonstrated no statistical difference. PCS patients had a significantly more valgus preoperative alignment, greater change in posterior femoral offset and smaller patellar component size. PCS is a relatively common complication following TKA. Arthroscopy yields functional results comparable to controls. Radiographic and technical factors are associated with PCS.

Negative pressure wound therapy is associated with resolution of incisional drainage in most wounds after hip arthroplasty.

BACKGROUND: Persistent wound drainage after hip arthroplasty is a risk factor for periprosthetic infection. Negative pressure wound therapy (NPWT) has been used in other fields for wound management although it is unclear whether the technique is appropriate for total hip arthroplasty. QUESTIONS/PURPOSES: We determined (1) the rate of wound complications related to use of NPWT for persistent incisional drainage after hip arthroplasty; (2) the rate of resolution of incisional drainage using this modality; and (3) risk factors for failure of NPWT for this indication. METHODS: In a pilot study we identified 109 patients in whom NPWT was used after hip arthroplasty for treating postoperative incisional drainage between April 2006 and April 2010. On average, the NPWT was placed on postoperative Day 3 to 4 (range, 2-9 days) and applied for 2 days (range, 1-10 days). We then determined predictors of subsequent surgery. Patients were followed until failure or a minimum of 1 year (average, 29 months; range, 1-62 months). RESULTS: Eighty-three patients (76%) had no further surgery and 26 patients (24%) had subsequent surgery: 11 had superficial irrigation and débridement (I&D), 12 had deep I&D with none requiring further surgery, and three ultimately had component removal. Predictors of subsequent surgery included international normalized ratio level greater than 2, greater than one prior hip surgery, and device application greater than 48 hours. There were no wound-related complications associated with NPWT. CONCLUSIONS: The majority of our patients had cessation of wound drainage with NPWT. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.