Mutant SOD1 prevents normal functional recovery through enhanced glial activation and loss of motor neuron innervation after peripheral nerve injury.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is poorly understood with no effective therapeutics. One long entertained observation is that ALS may be precipitated focally by nerve injury. Many patients with ALS are athletes or veterans, and some have suffered nerve injuries at the site where ALS first presents. Here we explore how a genetic SOD1 mutation alters the inflammatory response and affects functional recovery after an environmental insult in a rat model. METHODS: Unilateral sciatic nerve crush injuries were performed in SOD1 G93A rats prior to disease symptom onset. Functional recovery was compared between injured wild-type littermates and uninjured SOD1 rats. Spinal cord tissues were analyzed quantitatively for SOD1 expression, glial reactivity, and motor neuron synaptic integrity. RESULTS: Injured SOD1 rats failed to recover and showed hastened functional decline with decreased survival. Injury induced extracellular SOD1 expression was associated with heightened, prolonged microglial and astrogial activation in the ventral horn. This inflammatory response spread to uninjured motor neuron pools and was associated with increased motor neuron synaptic loss. DISCUSSION: This study identified a relationship between genetic and environmental contributions to disease onset and progression in ALS. The findings suggest that injury induced SOD1 mutant protein induces a heightened and prolonged inflammatory response resulting in motor neuron degeneration through synaptic loss. Once initiated, this process spreads to adjacent motor neurons leading to contiguous spread of the disease. Treatments that suppress this heightened glial response could slow disease progression in ALS patients with focal sites of disease onset. SIGNIFICANCE STATEMENT: The contribution of environmental factors such as peripheral nerve insults in ALS is not well understood. Here we examined the effect of a single sciatic nerve injury in SOD1 (G93A) rats to explore the contribution of this environmental insult on disease onset and progression. After the injury, SOD1 animals failed to recover and had a more rapid functional decline. Histopathologically, SOD1 animals had heightened SOD1 expression, microglial and astroglial responses, and a reduction of motor neuron innervation. Taken together, these results provide a plausible mechanism of how the SOD1 mutated protein promotes an abnormal response to injury that leads to neurodegenerative changes in an ALS model that is amenable to therapeutic testing.

New Single-stage Double Osteotomy for Late-presenting Infantile Tibia Vara: A Comprehensive Approach.

BACKGROUND: Successful surgical treatment of late-presenting infantile tibia vara (ITV) patient requires the correction of oblique deformities. The purpose of this study was to report on a new comprehensive approach to correct and prevent recurrence of these deformities with a single procedure. METHODS: Medical records of 23 consecutive children (7 to 18 y) with advanced ITV (29 knees) were retrospectively reviewed after a mean of 7.3 years postoperatively (range, 2 to 22 y). Indications for the corrective surgery were any child 7 year or older with a varus mechanical axis angle ≥10 degrees or a varus anatomic axis angle ≥11 degrees and a medial tibial angle (MTA) slope <60 degrees. The deformities were corrected with a dome-shaped osteotomy proximal to the tibial tubercle with a midline vertical extension to the subchondral region of the joint and a lateral hemi-epiphysiodesis. RESULTS: At latest follow-up, means and medians of each tibial radiographic axis measurement improved significantly from preoperative values (P<0.001): mechanical axis angle from 23 degrees to 4 degrees varus, anatomic axis angle from 25 degrees varus to 1 degree valgus, MTA downward slope from 30 to 78 degrees, posterior MTA from 59 to 80 degrees. In total, 79% and 74% had good to excellent results based on radiographic criteria and clinical questionnaire for satisfaction, pain and function, respectively. Two abnormal medial tibial plateau types were described. CONCLUSIONS: This is the first study to use a single-stage double osteotomy performed proximal to the tibial tubercle for the late-presenting ITV for children 7 years of age or older. In addition to the effective correction of the 4 major tibial deformities, a lateral proximal tibial hemi-epiphysiodesis minimizes recurrence of tibia vara. A contralateral proximal tibial epiphysiodesis is recommended for treated skeletally immature patients with unilateral disease. LEVEL OF EVIDENCE: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence.

Blood Transfusion After Primary Total Hip Arthroplasty: National Trends and Perioperative Outcomes.

The purpose of this study was to quantify the changes in transfusion rates, both allogeneic blood transfusion (ALBT) and autogenic blood transfusion (ATBT) on a national scale, and determine patient factors associated with transfusions. The National Hospital Discharge Survey was evaluated between 2001 and 2010 for primary total hip arthroplasty (THA) patients and categorized on the basis of transfusion necessity, type, and comorbidity burden. A logistic regression comparison of ALBT, ATBT, and nontransfused patients was performed with respect to patient demographics and in-hospital complications. The proportion of patients requiring any transfusion decreased from an average rate of 22.8% between 2001 and 2005 to 21.2% between 2006 and 2010 (p = .01). ATBT rates decreased (r = -.99) from 11.0% in 2001 to 2.8% in 2010. ALBT rates increased (r = .66) from 14% in 2001 to 16.6% in 2010. The number of patients requiring a blood transfusion after THA decreased in the United States with a trend shifting from ATBT to ALBT. (Journal of Surgical Orthopaedic Advances 26(4):216-222, 2017).

Revision total hip arthroplasty in the United States: national trends and in-hospital outcomes.

PURPOSE: With the increasing number of primary total hip arthroplasties (THA) being performed, the frequency of revision surgery is also expected to increase. We analysed the immediate in-hospital complications and epidemiologic data of 3,469 revision and 18,186 primary THA cases. METHODS: The National Hospital Discharge Survey (NHDS) was evaluated between 2001 and 2010 for patients who underwent revision and primary THA. Patients were identified and included in our retrospective study based on ICD-9 procedure codes. RESULTS: The number of primary and revision THAs increased steadily from 2001 to 2010. The revision burden decreased for the same studied period (r = -0.92) to reach 13.9 % in 2010. The South region had higher revision burden of 17.4 % (p < 0.001). The primary THA group was more likely to be obese, morbidly obese, and have hypertension (p < 0.001). The revision THA group had an increased rate of blood transfusions (p < 0.001), deep venous thrombosis (p = 0.008), post-operative sepsis (p < 0.001), and wound complications (p < 0.001). The in-hospital mortality rate was also higher for the revision THA group (0.6 % versus 0.2 %, p < 0.001). CONCLUSIONS: The revision burden has undergone a steady decrease over the ten years studied and the reason for this is likely multifactorial. The South region had a significantly higher revision burden when compared to the rest of the United States. Larger hospitals tend to perform relatively more revisions. Revision THA patients are associated with longer hospital stay, higher complications rate, and higher in-hospital mortality rate.

Mechanical Properties of the Human Tibial and Peroneal Nerves Following Stretch With Histological Correlations.

Despite the extensive literature regarding peripheral nerve stretch injuries, there are few studies that compare the nerve histology with the mechanical properties in humans. There is clinical evidence suggesting that the peroneal nerve is at greater risk for injury compared to the tibial nerve following total hip arthroplasty and hip trauma. We examined the two nerves from fresh human cadavers with or without controlled stretch. The mechanical properties, stiffness, and strain were compared with light microscopic preparations in longitudinal sections stained by the trichrome method for collagen and showing the effects of structural deformation. The tibial nerve had an average failure load 1.7× that for the peroneal nerve (P = 0.0001). Although the corresponding average stiffness showed a trend toward being larger (4.39 vs. 3.81 N/mm), the difference was not significant (P = 0.126). Histologically, the perineurium along with the underlying nerve fascicle was undulated in the control specimens and straightened out in the stretched specimens. Peroneal nerves went on to failure at lower loads and exhibited a wavy pattern on pathologic slides after failure, which shows that peroneal nerves fail mechanically before they can unfold. The tibial nerve has a biomechanical and histological advantage compared to the peroneal nerve during tensile testing, which could be the reason why it is less commonly damaged. We conclude that the perineurium is especially protective against deformation changes in human nerves relative to the respective nerve size and number of fascicles. Anat Rec, 302:2030-2039, 2019. © 2019 American Association for Anatomy.

Knee Arthrodesis Outcomes After Infected Total Knee Arthroplasty and Failure of Two-stage Revision With an Antibiotic Cement Spacer.

BACKGROUND: Reinfected total knee arthroplasty can be managed with a second two-stage exchange or a knee arthrodesis procedure. METHODS: Twenty-three patients with knee arthrodesis after failed exchange arthroplasty for infection were reviewed. Patients were managed with a staged protocol of implant extraction, débridement, and implantation of an antibiotic spacer, with subsequent arthrodesis. Follow-up averaged 40.4 months, with a minimum of 1 year. RESULTS: Bony union with eradication of infection was achieved in 20/23 knees. Sixteen of the 20 patients were able to ambulate with minimal pain. The average time to union was 11.3 months, and the average leg length discrepancy was 4.85 cm. The average Knee Society Score after arthrodesis was 44, and the average visual analog scale pain score was 1.73. Three patients underwent above-knee amputation. DISCUSSION: Knee arthrodesis performed for persistent periprosthetic infection allowed for eradication of infection and union in 87% of the patients, creating a stable knee fusion.