Comparison of Loss of Bone Height Following Total Ankle Arthroplasty Versus Tibiotalocalcaneal Arthrodesis.

Ankle arthrodesis and total ankle arthroplasty are both well-accepted surgical treatment options for end-stage ankle arthrosis. However, total ankle arthroplasty has gained popularity as the survivability of implants is improving. It is understood that there is loss of bone height following tibiotalocalcaneal arthrodesis, but to our knowledge, this has not been investigated in the setting of total ankle arthroplasty. A retrospective radiographic review was conducted over a 5-year period. We investigated all patients who underwent a tibiotalocalcaneal arthrodesis or total ankle arthroplasty for treatment of ankle arthritis by a single fellowship-trained orthopedic surgeon. The anterior and posterior height measurements were measured on preoperative and postoperative lateral radiographs. Differences between preoperative and postoperative heights were analyzed through a series of analyses of covariance. One hundred and thirty-three patients and 143 operative extremities were included: 71 operative extremities in the tibiotalocalcaneal arthrodesis group (mean age 55.5 ± 13.3 years, BMI 32.2 ± 7.9) and 72 in the total ankle arthroplasty group (mean age 65.4 ± 9.5 years, BMI 30.7 ± 6.4). Statistical analysis demonstrated a loss of height in the tibiotalocalcaneal arthrodesis group, and an increased anterior and posterior height in the total ankle arthroplasty group. However, when comparing the arthroplasty group and arthrodesis group only the anterior height measurement reached statistical significance when stratified by gender (p < .001). The potential change in height is an important factor to consider during surgical planning as a limb length discrepancy may result.

Change in Height Following Tibiotalocalcaneal Arthrodesis: Retrospective Radiographic Analysis.

Tibiotalocalcaneal arthrodesis (TTCA) with an intramedullary rod is a viable treatment option for a myriad of pathologies involving the foot and ankle. While the current literature has focused on fixation techniques, deformity correction, and clinical outcomes, we are unaware of any studies specifically examining change in height following a TTCA. In the present study, we retrospectively analyzed radiographs with novel radiographic techniques to determine the change in height from preoperative to postoperative radiographs following TTCA. Patients were divided into 3 categories: Charcot, arthritis, and pes planus as the indication for surgical intervention. We found that Charcot and arthritis had an average decrease in height on anterior and posterior measurements of the height from the distal tibia to the calcaneus, while pes planus had an increase in height. The average Charcot change in height was -12.0 ± 24.4 mm anteriorly and -7.6 ± 15.5 mm posteriorly. The average change in height for the arthritis group was -6.9 ± 6.7 mm anteriorly and -3.8 ± 5.8 mm posteriorly. The pes planus group was found to have an average increase in height 0.5 ± 8.0 mm anteriorly and 2.9 ± 5.8 mm posteriorly. Overall, we found a statistically significant difference in height change between the 3 groups in anterior measurements (p = .012) and posterior measurement (p = .006). We recommend surgeons who perform this procedure to be aware of the potential change in height to better tailor surgical and postoperative care.

Opioid Prescribing Patterns of Foot and Ankle Surgeons: Single State Review.

The United States is currently in an opioid crisis. In order improve the amount of misuse and overdoses from opioids, some institutions have begun to create protocols based off of state and federal opioid prescription regulations. Our purpose is to analyze the current opioid prescribing patterns in foot and ankle surgery and create an institutional protocol. A survey on current opioid prescribing patterns based on the podiatric surgery was sent out from November 20, 2020 to January 11, 2021 to all members of the North Carolina Foot and Ankle Society. One-hundred surgeons participated in the survey. The most commonly prescribed postoperative pain medication was Hydrocodone/acetaminophen 5 mg/325 mg and the most common quantity was between 21 and 30 tablets. The most common medication for local blocks reported was bupivacaine and lidocaine mixed performed as a block closest to the surgical site. We recommend creating an institutional based opioid protocol for foot and ankle surgeries based off of the procedure performed by the surgeon. We recommend limiting prescriptions to under 30 tablets and utilizing a local or regional pain block for podiatric surgeries.

Primary Arthrodesis versus Open Reduction and Internal Fixation for Lisfranc Joint Fracture-Dislocations in Adults: A Systematic Review.

BACKGROUND: The Lisfranc joint is an intricate podiatric medical structure that when injured can prove difficult to treat. No consensus has been established on optimal surgical management for this injury. It is widely debated whether open reduction and internal fixation or primary arthrodesis provides better outcomes for patients. Although literature has been published on this subject, no generalized guidelines have been created. The goal of this study was to analyze high-level meta-analyses to draw conclusions about surgical interventions for Lisfranc joint injuries. METHODS: A literature review was conducted to analyze outcomes of meta-analyses from January 1, 2016, to August 31, 2021. Only high-level evidence that reported at least one of the following outcomes was included: American Orthopaedic Foot and Ankle Society scale score, visual analog scale score, total complication rate, hardware removal rate, revision surgery rate, and secondary procedure rate. RESULTS: Six articles met the inclusion and exclusion criteria and were then analyzed. For all of the outcome measures, primary arthrodesis was equal or superior to open reduction and internal fixation. CONCLUSIONS: We recommend primary arthrodesis over open reduction and internal fixation for adult Lisfranc injuries.

Motoneurons secrete angiogenin to induce RNA cleavage in astroglia.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.

Intermediate to Long-Term Follow-up of the Salto Talaris Fixed-Bearing Total Ankle Prosthesis.

BACKGROUND: Total ankle arthroplasty (TAA) remains a viable option for recalcitrant, end-stage ankle arthritis. Among the various Food and Drug Administration (FDA)-approved prosthetic options is the fixed-bearing Salto Talaris implant. The aim of the present study was to evaluate the intermediate to long-term clinical outcomes and radiographic complications following implantation of the Salto Talaris TAA. METHODS: Nineteen Salto Talaris total ankle implants were included in the present retrospective study. Medical records were reviewed to determine pre- and postoperative visual analog scale (VAS) pain scores, and both medical records and radiographs were utilized to assess for complications. Telephone interviews were then conducted to assess for overall patient satisfaction. RESULTS: At a mean follow of 6.9 years (range, 3.5-12 years), there was a 21% complication rate according to the classification system described by Glazebrook et al. The reoperation rate was low at 10.5%, and there was 100% survivorship of the total ankle implant. The average pain decreased from 9.1 (range, 7-10) preoperatively to 2.6 (range, 0-10) postoperatively. Patients reported a 95% satisfaction rate, and 16% of patients reported using a brace postoperatively. CONCLUSION: The Salto Talaris arthroplasty was associated with low complication and reoperation rates, and a high survivorship at intermediate to long-term follow-up. LEVELS OF EVIDENCE: 4.

Vascularized Pedicled Fibula for Pediatric Tibia Reconstruction.

SUMMARY: This video reviews the technique of a vascularized fibula flap for pediatric tibia reconstruction. A 4-year-old boy with a history of a left tibial infected nonunion status after multiple debridements presented with segmental bone loss and difficulty with ambulation. An ipsilateral vascularized fibula flap was used for reconstruction. The patient proceeded to union and was independently ambulatory with bracing.

Cytoplasmic inclusions of Htt exon1 containing an expanded polyglutamine tract suppress execution of apoptosis in sympathetic neurons.

Proteins containing extended polyglutamine repeats cause at least nine neurodegenerative disorders, but the mechanisms of disease-related neuronal death remain uncertain. We show that sympathetic neurons containing cytoplasmic inclusions formed by 97 glutamines expressed within human huntingtin exon1-enhanced green fluorescent protein (Q97) undergo a protracted form of nonapoptotic death that is insensitive to Bax deletion or caspase inhibition but is characterized by mitochondrial dysfunction. By treating the neurons with combined cytosine arabinoside and NGF withdrawal, we demonstrate that Q97 confers a powerful resistance to apoptosis at multiple levels: despite normal proapoptotic signaling (elevation of P-ser15-p53 and BimEL), there is no increase of Puma mRNA or Bax activation, both necessary for apoptosis. Even restoration of Bax translocation with overexpressed Puma does not activate apoptosis. We demonstrate that this robust inhibition of apoptosis is caused by Q97-mediated accumulation of Hsp70, which occurs through inhibition of proteasomal activity. Thus, apoptosis is reinstated by short hairpin RNA-mediated knockdown of Hsp70. These findings explain the rarity of apoptotic death in Q97-expressing neurons. Given the proteasomal blockade, we test whether enhancing lysosomal-mediated degradation with rapamycin reduces Q97 accumulation. Rapamycin reduces the amount of nonpathological Q25 by 70% over 3 d, but Q97 accumulation is unaffected. Interestingly, Q47 inclusions form more slowly as a result of constitutive lysosomal degradation, but faster-forming Q97 inclusions escape lysosomal control. Thus, cytoplasmic Q97 inclusions are refractory to clearance by proteasomal and lysosomal systems, leading to a toxicity that dominates over neuroprotective Hsp70. Our findings may explain the rarity of apoptosis but the inevitable cell death associated with polyQ inclusion diseases.

Control of motoneuron survival by angiogenin.

Mutations in the hypoxia-inducible factor angiogenin (ANG) have been identified in Amyotrophic Lateral Sclerosis (ALS) patients, but the potential role of ANG in ALS pathogenesis was undetermined. Here we show that angiogenin promotes motoneuron survival both in vitro and in vivo. Angiogenin protected cultured motoneurons against excitotoxic injury in a PI-3-kinase/Akt kinase-dependent manner, whereas knock-down of angiogenin potentiated excitotoxic motoneuron death. Expression of wild-type ANG protected against endoplasmic reticulum (ER) stress-induced and trophic-factor-withdrawal-induced cell death in vitro, whereas the ALS-associated ANG mutant K40I exerted no protective activity and failed to activate Akt-1. In SOD1(G93A) mice angiogenin delivery increased lifespan and motoneuron survival, restored the disease-associated decrease in Akt-1 survival signaling, and reversed a pathophysiological increase in ICAM-1 expression. Our data demonstrate that angiogenin is a key factor in the control of motoneuron survival.

FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans.

We report on 2 patients with compound heterozygous mutations in forkhead box N1 (FOXN1), a transcription factor essential for thymic epithelial cell (TEC) differentiation. TECs are critical for T cell development. Both patients had a presentation consistent with T-/loB+NK+ SCID, with normal hair and nails, distinct from the classic nude/SCID phenotype in individuals with autosomal-recessive FOXN1 mutations. To understand the basis of this phenotype and the effects of the mutations on FOXN1, we generated mice using CRISPR-Cas9 technology to genocopy mutations in 1 of the patients. The mice with the Foxn1 compound heterozygous mutations had thymic hypoplasia, causing a T-B+NK+ SCID phenotype, whereas the hair and nails of these mice were normal. Characterization of the functional changes due to the Foxn1 mutations revealed a 5-amino acid segment at the end of the DNA-binding domain essential for the development of TECs but not keratinocytes. The transcriptional activity of this Foxn1 mutant was partly retained, indicating a region that specifies TEC functions. Analysis of an additional 9 FOXN1 mutations identified in multiple unrelated patients revealed distinct functional consequences contingent on the impact of the mutation on the DNA-binding and transactivation domains of FOXN1.

Rapamycin inhibits polyglutamine aggregation independently of autophagy by reducing protein synthesis.

Accumulation of misfolded proteins and protein assemblies is associated with neuronal dysfunction and death in several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease (HD). It is therefore critical to understand the molecular mechanisms of drugs that act on pathways that modulate misfolding and/or aggregation. It is noteworthy that the mammalian target of rapamycin inhibitor rapamycin or its analogs have been proposed as promising therapeutic compounds clearing toxic protein assemblies in these diseases via activation of autophagy. However, using a cellular model of HD, we found that rapamycin significantly decreased aggregation-prone polyglutamine (polyQ) and expanded huntingtin and its inclusion bodies (IB) in both autophagy-proficient and autophagy-deficient cells (by genetic knockout of the atg5 gene in mouse embryonic fibroblasts). This result suggests that rapamycin modulates the levels of misfolded polyQ proteins via pathways other than autophagy. We show that rapamycin reduces the amount of soluble polyQ protein via a modest inhibition of protein synthesis that in turn significantly reduces the formation of insoluble polyQ protein and IB formation. Hence, a modest reduction in huntingtin synthesis by rapamycin may lead to a substantial decrease in the probability of reaching the critical concentration required for a nucleation event and subsequent toxic polyQ aggregation. Thus, in addition to its beneficial effect proposed previously of reducing polyQ aggregation/toxicity via autophagic pathways, rapamycin may alleviate polyQ disease pathology via its effect on global protein synthesis. This finding may have important therapeutic implications.

Multiple risk behavior and injury: an international analysis of young people.

BACKGROUND: Multiple risk behavior plays an important role in the social etiology of youth injury, yet the consistency of this observation has not been examined multinationally. OBJECTIVE: To examine reports from young people in 12 countries, by country, age group, sex, and injury type, to quantify the strength and consistency of this association. SETTING: World Health Organization collaborative cross-national survey of health behavior in school-aged children. PARTICIPANTS: A multinational representative sample of 49 461 students aged 11, 13, and 15 years. MAIN EXPOSURE MEASURES: Additive score consisting of counts of self-reported health risk behaviors: smoking, drinking, nonuse of seat belts, bullying, excess time with friends, alienation at school and from parents, truancy, and an unusually poor diet. MAIN OUTCOME MEASURE: Self-report of a medically treated injury. RESULTS: Strong gradients in risk for injury were observed according to the numbers of risk behaviors reported. Overall, youth reporting the largest number (> or =5 health risk behaviors) experienced injury rates that were 2.46 times higher (95% confidence interval, 2.27-2.67) than those reporting no risk behaviors (adjusted odds ratios for 0 to > or =5 reported behaviors: 1.00, 1.22, 1.48, 1.73, 1.98, and 2.46, respectively; P<.001 for trend). Similar gradients in risk for injury were observed among youth in all 12 countries and within all demographic subgroups. Risk gradients were especially pronounced for nonsports, fighting-related, and severe injuries. CONCLUSIONS: Gradients in risk for youth injury increased in association with numbers of risk behaviors reported in every country examined. This cross-cultural finding indicates that the issue of multiple risk behavior, as assessed via an additive score, merits attention as an etiological construct. This concept may be useful in future injury control research and prevention efforts conducted among populations of young people.

Gradients in risk for youth injury associated with multiple-risk behaviours: a study of 11,329 Canadian adolescents.

This study used the Canadian version of the World Health Organization-Health Behaviour in School-Aged Children (WHO-HBSC) Survey to examine the role of multiple risk behaviours and other social factors in the etiology of medically attended youth injury. 11,329 Canadians aged 11-15 years completed the 1997-1998 WHO-HBSC, of which 4152 (36.7%) reported at least one medically attended injury. Multiple logistic regression analyses failed to identify an expected association between lower socio-economic status and risk for injury. Strong gradients in risk for injury were observed according to the numbers of multiple risk behaviours reported. Youth reporting the largest number (7) of risk behaviours experienced injury rates that were 4.11 times (95% CI: 3.04-5.55) higher than those reporting no high risk behaviours (adjusted odds ratios for 0-7 reported behaviours: 1.00, 1.13, 1.49, 1.79, 2.28, 2.54, 2.62, 4.11; p(trend) < 0.001). Similar gradients in risk were observed within subgroups of young people defined by grade, sex, and socio-economic level, and within restricted analyses of various injury types (recreational, sports, home, school injuries). The gradients were especially pronounced for severe injury types and among those reporting multiple injuries. The analyses suggest that multiple risk behaviours may play an important role in the social etiology of youth injury, but these same analyses provide little evidence for a socio-economic risk gradient. The findings in turn have implications for preventive interventions.

Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin. BIOLOGICAL SIGNIFICANCE: This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying neurodegenerative disorders.

Does the school performance variable used in the International Health Behavior in School-Aged Children (HBSC) Study reflect students' school grades?

BACKGROUND: Given the pressure that educators and policy makers are under to achieve academic standards for students, understanding the relationship of academic success to various aspects of health is important. The international Health Behavior in School-Aged Children (HBSC) questionnaire, being used in 41 countries with different school and grading systems, has contained an item assessing perceived school performance (PSP) since 1986. Whereas the test-retest reliability of this item has been reported previously, we determined its convergent and discriminant validity. METHODS: This cross-sectional study used anonymous self-report data from Austrian (N = 266), Norwegian (N = 240), and Canadian (N = 9,717) samples. Students were between 10 and 17 years old. PSP responses were compared to the self-reported average school grades in 6 subjects (Austria) or 8 subjects (Norway), respectively, or to a general, 5-category-based appraisal of most recent school grades (Canada). RESULTS: Correlations between PSP and self-reported average school grade scores were between 0.51 and 0.65, representing large effect sizes. Differences between the median school grades in the 4 categories of the PSP item were statistically significant in all 3 samples. The PSP item showed predominantly small associations with some randomly selected HBSC items or scales designed to measure different concepts. CONCLUSIONS: The PSP item seems to be a valid and useful question that can distinguish groups of respondents that get good grades at school from those that do not. The meaning of PSP may be context-specific and may have different connotations across student populations from different countries with different school systems.

Characterization of Puma-dependent and Puma-independent neuronal cell death pathways following prolonged proteasomal inhibition.

Proteasomal stress and the accumulation of polyubiquitinated proteins are key features of numerous neurodegenerative disorders. Previously we demonstrated that stabilization of p53 and activation of its target gene, puma (p53-upregulated mediator of apoptosis), mediated proteasome inhibitor-induced apoptosis in cancer cells. Here we demonstrated that Puma also contributed to proteasome inhibitor-induced apoptosis in mouse neocortical neurons. Although protection afforded by puma gene deletion was incomplete, we found little evidence indicating contributions from other proapoptotic BH3-only proteins. Attenuation of bax expression did not further reduce Puma-independent apoptosis, suggesting that pathways other than the mitochondrial apoptosis pathway were activated. Real-time imaging experiments in wild-type and puma-deficient neurons using a fluorescence resonance energy transfer (FRET)-based caspase sensor confirmed the involvement of a second cell death pathway characterized by caspase activation prior to mitochondrial permeabilization and, more prominently, a third, caspase-independent and Puma-independent pathway characterized by rapid cell shrinkage and nuclear condensation. This pathway involved lysosomal permeabilization in the absence of autophagy activation and was sensitive to cathepsin but not autophagy inhibition. Our data demonstrate that proteasomal stress activates distinct cell death pathways in neurons, leading to both caspase-dependent and caspase-independent apoptosis, and demonstrate independent roles for Puma and lysosomal permeabilization in this model.

Amelioration of protein misfolding disease by rapamycin: translation or autophagy?

Rapamycin is an inhibitor of mTOR, a key component of the mTORC1 complex that controls the growth and survival of cells in response to growth factors, nutrients, energy balance and stresses. The downstream targets of mTORC1 include ribosome biogenesis, transcription, translation and macroautophagy. Recently it was proposed that rapamycin and its derivatives enhance the clearance (and/or reduce the accumulation) of mutant intracellular proteins causing proteinopathies such as tau, alpha-synuclein, ataxin-3, and full-length or fragments of huntingtin containing a polyglutamine (polyQ) expansion, by upregulating macroautophagy. We tested this proposal directly using macroautophagy-deficient fibroblasts. We found that rapamycin inhibits the aggregation of a fragment of huntingtin (exon 1) containing 97 polyQs similarly in macroautophagy-proficient (Atg5(+/+)) and macroautophagy-deficient (Atg5(-/-)) cells. These data demonstrate that autophagy is not the only mechanism by which rapamycin can alleviate the accumulation of misfolded proteins. Our data suggest that rapamycin inhibits mutant huntingtin fragment accumulation due to inhibition of protein synthesis. A model illustrates how a modest reduction in polyQ synthesis can lead to a long-lasting reduction in polyQ aggregation. We propose that several mechanisms exist by which rapamycin reduces the accumulation and potential toxicity of misfolded proteins in diseases caused by protein misfolding and aggregation.

Overweight and obesity in Canadian adolescents and their associations with dietary habits and physical activity patterns.

PURPOSE: To present recent overweight and obesity prevalence rates for 11-16-year-old Canadian youth and to examine associations between overweight and obesity with dietary habits and leisure-time physical activities. METHODS: Nationally representative sample of 11-16-year-old adolescents (n = 5890) from the Canadian component of the 2001/02 World Health Organization Health Behaviour in School-Aged Children Survey were used. Height, weight, dietary habits, and leisure-time activities were determined from self-report. Age- and gender-specific prevalence rates of overweight and obesity were calculated based on international body mass index cut-points. Logistic regression was employed to examine the association among measures of overweight, obesity, and lifestyle habits. RESULTS: Fifteen percent of 11-16-year-old Canadian youth were overweight (preobese) and 4.6% were obese in 2002. These prevalence rates were greater in boys than girls (p < .001), but did not vary according to age. There were no clear associations observed between dietary habits and measures of overweight and obesity. However, physical activity levels were lower (p < or = .05) and television viewing times were higher (p < .01) in overweight and obese boys and girls than normal-weight youth. CONCLUSIONS: The prevalence rates of overweight and obesity in Canadian youth are high. The results suggest that physical inactivity and sedentary behaviors are strongly related to obesity in Canadian adolescents.