Do Battlefield Injury-acquired Indwelling Metal Fragments Induce Metal Immunogenicity?

BACKGROUND: A battlefield-related injury results in increased local and systemic innate immune inflammatory responses, resulting in wound-specific complications and an increased incidence of osteoarthritis. However, little is known about whether severe injuries affect long-term systemic homeostasis, for example, immune function. Moreover, it also remains unknown whether battlefield-acquired metal fragments retained over the long term result in residual systemic effects such as altered immune reactivity to metals. QUESTIONS/PURPOSES: Does a retained metal fragment from a battlefield injury contribute to increased (1) adaptive metal-specific immune responses, (2) systemically elevated metal ion serum levels, and (3) serum immunoglobulin levels compared with combat injuries that did not result in a retained metal fragment? METHODS: In this pilot study, we analyzed metal-immunogenicity in injured military personnel and noninjured control participants using lymphocyte transformation testing (LTT, lymphocyte proliferation responses to cobalt, chromium and nickel challenge at 0.001, 0.01 and 0.1-mM concentrations in triplicate for each participant), serum metal ion analysis (ICP-mass spectroscopy), and serum immunoglobulin analysis (IgE, IgG, IgA, and IgM ). Military personnel with a battlefield-sustained injury self-recruited without any exclusion for sex, age, degree of injury. Those with battlefield injury resulting in retained metal fragments (INJ-FRAG, n = 20 male, mean time since injury ± SD was 12 ± 10 years) were compared with those with a battlefield injury but without retained metal fragments (INJ-NO-FRAG, n = 12 male, mean time since injury ± SD was 13 ± 12 years). A control group comprised of male noninjured participants was used to compare measured immunogenicity metrics (n = 11, males were selected to match battlefield injury group demographics). RESULTS: Military participants with sustained metal fragments had increased levels of metal-induced lymphocyte responses. The lymphocyte stimulation index among military participants with metal fragments was higher than in those with nonretained metal fragments (stimulation index = 4.2 ± 6.0 versus stimulation index = 2.1 ± 1.2 (mean difference 2.1 ± 1.4 [95% confidence interval 5.1 to 0.8]; p = 0.07) and an average stimulation index = 2 ± 1 in noninjured controls. Four of 20 participants injured with retained fragments had a lymphocyte proliferation index greater than 2 to cobalt compared with 0 in the group without a retained metal fragment or 0 in the control participants. However, with the numbers available, military personnel with retained metal fragments did not have higher serum metal ion levels than military participants without retained metal fragment-related injuries or control participants. Military personnel with retained metal fragments had lower serum immunoglobulin levels (IgG, IgA, and IgM) than military personnel without retained metal fragments and noninjured controls, except for IgE. Individuals who were metal-reactive positive (that is, a stimulation index > 2) with retained metal fragments had higher median IgE serum levels than participants who metal-reactive with nonmetal injuries (1198 ± 383 IU/mL versus 171 ± 67 IU/mL, mean difference 1027 ± 477 IU/mL [95% CI 2029 to 25]; p = 0.02). CONCLUSIONS: We found that males with retained metal fragments after a battlefield-related injury had altered adaptive immune responses compared with battlefield-injured military personnel without indwelling metal fragments. Military participants with a retained metal fragment had an increased proportion of group members and increased average lymphocyte reactivity to common implant metals such as nickel and cobalt. Further studies are needed to determine a causal association between exposure to amounts of retained metal fragments, type of injury, personnel demographics and general immune function/reactivity that may affect personal health or future metal implant performance. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Self-Citation Does Not Appear to Artificially Inflate Orthopaedic Journal Ranking.

Until recently the impact factor has been considered the tool of choice among the many available for evaluating the relative prestige of journals. However, the inclusion of self-citations in its calculation has led some to question its validity. The SCImago Journal Rank is a relatively new rating system that excludes self-citation. This study analyzed the top 30 orthopaedic journals to determine which journals had higher self-citation rates and if those rates had any correlation with their impact factors and SCImago Journal Ranks. The study verified that self-citing was more common in specialty journals compared with general orthopaedic journals (p D .002). The results demonstrate a more positive correlation between self-citation and SCImago Journal Rank than impact factor. This finding suggests that the impact factor's inclusion of self-citations should not be thought to artificially inflate the impact factor of the subspecialty journals that most commonly cite their own work. (Journal of Surgical Orthopaedic Advances 27(2):131-135, 2018).

Occlusion training: pilot study for postoperative lower extremity rehabilitation following primary total knee arthroplasty.

With continued emphasis on the value of healthcare, factors such as quality of life and patient reported outcomes are critical in evaluating high-demand procedures such as knee replacement surgery. Equally important to the surgery itself is maximizing the effectiveness and efficiency of the treatment, both preoperatively and postoperatively, which can have a significant effect the final outcome. Technical outcomes of total knee replacement are generally considered excellent; however, many patients continue to have postoperative pain, functional limitations, and low treatment satisfaction. The recovery process can be difficult and is often prolonged in older patient populations. Blood flow restriction (BFR) training is a resistance exercise performed with a venous tourniquet that stimulates local changes in muscle at low resistance. Herein we report on 3 patients who participated in BFR exercises as an adjunct to their normal physical therapy following total knee arthroplasty.

Outcomes of Lisfranc Injuries in an Active Duty Military Population.

BACKGROUND: Traumatic injuries to the tarsometatarsal or Lisfranc joints can be complex problems associated with long-term morbidity. Currently there is no clear consensus regarding optimal fixation methods. The purpose of this study was to evaluate the association between time from injury to treatment and treatment method with outcome. It is hypothesized that patients who underwent open reduction internal fixation (ORIF) more acutely would have higher return to duty rates. METHODS: This study is a retrospective review of 171 low-energy closed tarsometatarsal dislocations and fracture dislocations in patients identified using a Department of Defense trauma registry. Outcomes were defined as return to active duty and separation from service. Patients were categorized into cohorts by surgical treatment: ORIF, primary arthrodesis (PA), or having required a salvage arthrodesis (SA). RESULTS: The data demonstrate no significant difference between ORIF and PA as well as significantly lower return to duty rates in those who underwent SA. There was no association between increased time from injury to treatment and the observed outcomes. CONCLUSION: This study not only reinforces the importance of initial anatomic reduction and the poor outcomes of posttraumatic osteoarthritis but also suggests that SA portends poor outcomes in a highly active population. Most notably it found no significant difference in return to duty rates between ORIF and PA despite the inclusion of more "missed" and chronic injuries in the PA group. This suggests that PA may be a viable option in a young and active population regardless of treatment timing. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma.

microRNAs are noncoding RNAs inhibiting expression of numerous target genes, and a few have been shown to act as oncogenes or tumor suppressors. We show that microRNA-7 (miR-7) is a potential tumor suppressor in glioblastoma targeting critical cancer pathways. miR-7 potently suppressed epidermal growth factor receptor expression, and furthermore it independently inhibited the Akt pathway via targeting upstream regulators. miR-7 expression was down-regulated in glioblastoma versus surrounding brain, with a mechanism involving impaired processing. Importantly, transfection with miR-7 decreased viability and invasiveness of primary glioblastoma lines. This study establishes miR-7 as a regulator of major cancer pathways and suggests that it has therapeutic potential for glioblastoma.

Notch-1 regulates transcription of the epidermal growth factor receptor through p53.

The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (mRNA) and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 upregulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development.