Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.

Long-term outcomes of total elbow arthroplasty for distal humeral fracture: results from a prior randomized clinical trial.

BACKGROUND: Total elbow arthroplasty (TEA) is a reliable treatment for elderly patients with comminuted intra-articular distal humeral fractures. However, the longevity and long-term complications associated with this procedure are unknown. The objectives of this study were to examine long-term outcomes and implant survival in elderly patients undergoing TEA for fracture. METHODS: Patients from a previously published randomized controlled trial of 42 patients in which TEA was compared with open reduction-internal fixation (ORIF) were followed up long term. Patients were aged 65 years or older with comminuted intra-articular distal humeral fractures. Outcomes included patient-reported grading of function and pain, revision surgical procedures, and implant survival. RESULTS: Data were obtained for 40 patients, 15 treated with ORIF and 25 treated with TEA, with a mean follow-up period of 12.5 years for surviving patients and 7.7 years for deceased patients. The reoperation rate was 3 of 25 in the TEA group and 4 of 15 in the ORIF group (P = .39). Of the 25 patients with TEAs, only 1 required (early) revision arthroplasty; 7 were living with their original arthroplasty, and 15 died with a well-functioning implant in situ. Three were lost to follow-up. CONCLUSIONS: TEA is an effective and reliable procedure for the treatment of comminuted distal humeral fractures in the elderly patient. Our study reveals reliable implant long-term survival, with no patient requiring a late revision. For the majority of these patients, a well-performed TEA will give them a well-functioning elbow for life and will be the last elbow procedure required.

A retrospective cohort study of displaced segmental radial head fractures: is 2 mm of articular displacement an indication for surgery?

HYPOTHESIS: Many investigators agree that 2 mm of articular displacement is a reasonable indication for open reduction and internal fixation of Mason type II fractures of the radial head. However, there is no evidence to support that this degree of articular displacement is predictive of poor outcomes in conservatively treated fractures. We hypothesized there would be no difference between conservatively treated radial head fractures with greater 2 mm of displacement and those with less than 2 mm of displacement in terms of patient-reported or clinical outcomes. MATERIALS AND METHODS: We reviewed databases of all radial head fractures in our region. The primary outcomes were the Patient-Rated Elbow Evaluation and Disabilities of the Arm, Shoulder and Hand questionnaires. Secondary outcomes included radiologic radiocapitellar arthritis and range of motion (ROM) at follow-up. Postinjury treatment protocols, as well as patient factors, were examined for their effects on outcome. RESULTS: The results showed no significant difference in any outcome for conservatively treated radial head fractures with 2 mm (P = .8) or even 3 mm (P = .6) of articular displacement over a mean follow-up of 4.4 years. Early ROM and physiotherapy showed no significant differences in any outcome measure. Dominant hand injury showed no significant difference in patient-reported outcomes; however, ROM was significantly decreased on examination. CONCLUSIONS: This retrospective review suggests that fracture displacement of 2 to 3 mm is not necessarily an indication for surgical fixation in isolated fractures of the radial head. In addition, it appears that postinjury ROM/physiotherapy does not play a large role in improving patient outcome.

Traumatic Volar Carpal Instability Nondissociative: A Case Series.

Carpal instability nondissociative (CIND) involves disruption between carpal rows from injury to extrinsic and intrinsic wrist ligaments. CIND traumatic (CINDT) highlights the posttraumatic etiology of some of these cases and has been gaining increasing attention in the literature. We present four cases of CINDT-volar intercalated segmental instability (VISI). We diagnosed two adults with distal radius fractures and two adolescents with Galeazzi fractures, all treated surgically, who developed CINDT-VISI with radiolunate angles greater than 15° at 2 weeks after surgery. One adult had progressive deformity but was asymptomatic at 33 months. The other underwent volar capsular release at 1 year to improve alignment. One adolescent with a fixed deformity required soft tissue releases and temporary pinning to restore alignment at 7 months. We treated the other successfully with early physiotherapy. No patient had radiographic signs of arthritis at 1-2 years. This is the first reported association between Galeazzi fractures and CINDT-VISI. Contrary to existing literature, we report successful outcomes with nonsurgical and delayed nonfusion surgery of CINDT-VISI.

Scapholunate Ligament Injury and the Effect of Scaphoid Lengthening.

Objective We hypothesized that lengthening the scaphoid in a model of scapholunate ligament injury (SLI) will result in correction of radiographic markers of dorsal intercalated segment instability (DISI) deformity. Materials and Methods An SLI with DISI deformity was created by sectioning the SL ligament, the palmar radiocarpal ligaments, and scapho-trapezio-trapezoid ligaments of a cadaveric upper extremity ( n = 5). The wrist was radiographed in both anteroposterior and lateral planes to confirm creation of SLI and DISI. The scaphoid was then osteotomized at its waist. A series of grafts (1-8 mm) were then placed at the osteotomy site. Radiographs were completed at each length. The main outcome measures were scapholunate interval (SL, mm), scapholunate angle (SLA, degrees), and radiolunate angle (RLA, degrees). These values, measured following the insertion of varying graft lengths, were compared with baseline measurements taken "post-injury" status. Results The ability to create an SLI with DISI was confirmed in the postinjury group with a statistically significant change in RLA, SLA, and SL compared with preinjury. With osteotomy and progressive insertion of spacers, the values improved into the accepted normal ranges for RLA (6 mm) and SLA (4 mm) with scaphoid lengthening. Conclusions In this cadaveric model of SL injury, radiographic markers of DISI were returned to within normal ranges with scaphoid osteotomy and lengthening. Clinical Relevance The results of this study add insight into wrist kinematics in our injury model and may represent a potential future direction for surgical treatment of SLI.

Clavicular Refracture at the Site of Angular Malunion in Young Athletes.

OBJECTIVE: The treatment of midshaft clavicle fractures has, in the last 2 decades, shifted markedly towards operative management. Prospective trials have defined accepted clinical and radiographic indications for the surgical management of clavicle fractures. This report documents 3 cases of clinically united angular malunion of the midshaft clavicle in young athletes that subsequently refractured to highlight angular deformity in the absence of displacement as a potential indication for surgical fixation. DESIGN: Case series. SETTING: A level 1 trauma centre. PATIENTS/PARTICIPANTS: Three young athletic patients with angular malunion of the midshaft clavicle who experienced refracture, requiring surgical fixation. INTERVENTION: Surgical fixation of midshaft clavicle fracture, as treatment for refracture after angular malunion. RESULTS: All 3 patients required subsequent surgical fixation of their midshaft clavicle fracture, correcting the angular malunion and restoring shoulder function. CONCLUSIONS: Midshaft clavicular fractures that malunite with significant angulation in the absence of displacement represent a risk for subsequent refracture. For this reason, angular deformity should be considered as a potential indication for surgical fixation in acute clavicular fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Segond fractures: not necessarily pathognemonic of anterior cruciate ligament injury in the pediatric population.

Initially described following cadaveric studies in the late 19th century by Dr. Paul Segond, the Segond fracture is now widely accepted as a pathognemonic radiographic marker of anterior cruciate ligament injury. This fracture in a skeletally immature 16-year-old was not seen with an anterior cruciate ligament injury, but with a Salter-Harris type IV fracture of the tibial plateau. A nonweightbearing knee immobilizer with the leg in full extension was used for 6 weeks. Recovery was uncomplicated, and range of motion and weightbearing began at 6 weeks.

Electrical stimulation of intact peripheral sensory axons in rats promotes outgrowth of their central projections.

A lesion of a peripheral nerve before a second injury (conditioning lesion, CL), enhances peripheral and central regeneration of dorsal root ganglion (DRG) axons. This effect is mediated by elevated neuronal cAMP. Here we wanted to investigate whether electrical stimulation (ES) of an intact nerve, which has been shown to accelerate peripheral axon outgrowth, is also effective in promoting axon regeneration of injured DRG axons in vitro and of the central DRG axons in vivo and, whether this effect is mediated by elevation of cAMP. For the in vitro assay, the intact sciatic nerve of adult rats was stimulated at 20 Hz for 1 h, 7 days before harvest and primary culture of DRG neurons on a growth permissive substrate. In the in vivo study, the central axons of the lumbosacral DRGs were cut in the Th8 dorsal column, and the sciatic nerve was either cut or left intact, and subjected to 1 h ES at 20 Hz or 200 Hz. In vitro, ES increased neurite outgrowth 4-fold as compared to non-stimulated DRG neurons. In vivo, ES at 20 Hz significantly increased axon outgrowth into the central lesion site as compared to the Sham control. The 20 Hz ES was as effective as the CL in increasing axon outgrowth into the lesion site but not in promoting axonal elongation even though 20 Hz ES increased intracellular cAMP levels in DRG neurons as effectively as the CL. Thus elevation of cAMP may account for the central axonal outgrowth after ES and a CL.

Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate.

OBJECTIVE: To investigate whether or not it is the frustrated growth state (no axon growth) that reduces regenerative capacity or the inability of axotomized motoneurons to remake muscle connections (axon growth-no muscle contact) that accounts for poor regenerative capacity of chronically axotomized motoneurons. METHODS: We chronically axotomized rat femoral motoneurons for 2 months by cutting the nerve and either capping the proximal nerve to prevent axon regeneration (Group 1, no axon growth for 2 mo) or encouraging axon regeneration but not target reinnervation by suture to the distal stump of cut saphenous nerve (Group 2, axon growth with no muscle contact). In the control fresh axotomy group (axon growth with muscle contact), femoral nerve stumps were resutured immediately. Two months later, the femoral nerve was recut and sutured immediately to encourage regeneration in a freshly cut saphenous nerve stump for 6 weeks. Regenerating axons in the saphenous nerve were back-labeled with fluorogold for enumeration of the femoral motoneurons that regenerated their axons into the distal nerve stump. RESULTS: We found that significantly fewer chronically axotomized motoneurons regenerated their axons than freshly axotomized motoneurons that regenerated their axons to reform nerve-muscle connections in the same length of time. The number of motoneurons that regenerated their axons was reduced in both the conditions of no axon growth and axon growth with no muscle contact; thus chronic axotomy for a 2-month period reduced regenerative success irrespective of whether the motoneurons were prevented from regenerating or encouraged to regenerate their axons in that same period of time. CONCLUSION: Axonal regeneration does not protect motoneurons from the negative effects of prolonged axotomy on regenerative capacity. It is the period of chronic axotomy, in which motoneurons remain without target nerve-muscle connection, and not simply a state of frustrated growth that accounts for the reduced regenerative capacity of those neurons.