Citations

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

Background: There is debate regarding the role of single-anesthetic versus staged bilateral total hip arthroplasty (THA) for patients with end-stage bilateral osteoarthritis. Studies have shown that single-anesthetic bilateral THA is associated with systemic complications, but there are limited data comparing patient outcomes in a matched setting of bilateral THA. Methods: We identified 94 patients (188 hips) who underwent single-anesthetic bilateral THA. Fifty-seven percent of the patients were male. Patients had a mean age of 52.2 years and body mass index of 27.1 kg/m 2 . They were matched 1:1 on the basis of sex, age (±1 year), and year of surgery (±3 years) to a cohort of patients undergoing staged bilateral THA. In the staged group, there was <1 year between procedures (range, 5 days to 10 months). Mean follow-up was 4 years for each group. Results: Patients in the single-anesthetic group experienced shorter total operating room time and length of stay. There was no difference (hazard ratio [HR] = 0.73, p = 0.50) in the overall revision-free survival in patients undergoing single-anesthetic or staged bilateral THA. The risks of reoperation (HR = 0.69, p = 0.40), complications (HR = 0.83, p = 0.48), and mortality (HR = 0.47, p = 0.10) were similar. Single-anesthetic bilateral THA reduced the total cost of care (by 27%, p = 0.0001). Conclusions: In this matched cohort analysis, single-anesthetic bilateral THA was not associated with an increased risk of revision, reoperation, or postoperative complications, while decreasing cost. In our experience, single-anesthetic bilateral THA is a safe procedure that, for certain patients, offers an excellent means to deal with bilateral hip osteoarthritis. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

A number of traditional medicine plants are hepatotoxic. Thus, while the traditional uses of Atuna racemosa suggest little indication for toxicity, it is nonetheless important to examine the potential for this extract to target the liver. Using Jurkat T cells and HepG2 hepatocytes as a model, the potential hepatotoxicity of this extract was evaluated. The results of a conditioned media experiment suggest that A. racemosa extract would likely be detoxified by the liver. These results provide the necessary background to Initiate an in vivo toxicology investigation.

SummaryBackgroundTherapy for coeliac disease (CD) mainly relies on following a gluten‐free diet (GFD); however, a serum marker for gluten intake has yet to be established.AimTo evaluate the utility of alkylresorcinol concentrations for detecting gluten intake in studies of human and mouse.MethodsAlkylresorcinol concentrations were compared among treated patients with coeliac disease (n = 34), untreated coeliac disease patients (n = 36) and controls (n = 33). Furthermore, seven additional coeliac disease patients whose serum samples were available at diagnosis and after GFD were evaluated. In mice studies, alkylresorcinol concentrations were compared in the serum of five mice fed a regular chow and 10 mice fed lifelong with a gluten‐free chow. In addition, the effect of adding gluten on changes of alkylresorcinol concentrations was also evaluated.ResultsTotal alkylresorcinol concentrations were significantly lower in treated with coeliac disease [median (IQR), 3 (2–8) nmol/L], compared to untreated patients [median (IQR), 32 (11–74) nmol/L; P < 0.0001] or healthy controls [median (IQR), 54 (23–112) nmol/L; P < 0.0001]. Moreover, alkylresorcinol concentrations in coeliac disease patients significantly decreased after introduction of a GFD (median, 34 nmol/L at diagnosis vs. 5 nmol/L after GFD, P = 0.02). In the mice, median (IQR) total alkylresorcinol concentrations in serum samples of mice fed lifelong with a gluten‐free chow was 1.8 (1.6–2.3) nmol/L, which was further significantly increased to 16 (11–22) nmol/L after 8 days of feeding with the gluten‐free chow that had gluten added to it. (P = 0.008).ConclusionSerum alkylresorcinol concentrations could be a useful marker for dietary gluten in coeliac disease.

ObjectiveTo describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects.MethodsWe conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids.ResultsAll guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid‐specific recommendations but also guideline quality in general.ConclusionCurrent recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly.

Background: High body mass index (BMI) is associated with increased rates of complications after total knee arthroplasty. To date, to our knowledge, studies have examined risk as a dichotomous variable using specific BMI thresholds. The purpose of this investigation was to quantify implant survival and the risk of common complications after total knee arthroplasty using BMI as a continuous variable. Methods: Using prospectively collected data from our institutional total joint registry, we analyzed 22,289 consecutive knees, in 16,136 patients, treated with primary total knee arthroplasty from 1985 to 2012. The mean BMI of these patients at the time of the surgical procedure was 31.3 kg/m 2 (range, 11 to 69 kg/m 2 ). The Kaplan-Meier survival method was used to estimate survivorship, reoperations, and common complications, with associations of outcomes assessed using a Cox regression model. Results: Utilizing smoothing spline parameterization, we found that reoperation (p < 0.001) and implant revision or removal rates (p < 0.001) increased with increasing BMI after total knee arthroplasty. Increasing BMI also was associated with increased rates of wound infection (hazard ratio [HR], 1.07; p < 0.001) and deep infection (HR, 1.08; p < 0.001) per unit of BMI over 35 kg/m 2 . A BMI of 35 to 40 kg/m 2 was associated with a higher rate of implant revision for aseptic loosening (p < 0.001) and for polyethylene wear (p < 0.001) compared with a BMI of 18 to 24.99 kg/m 2 . There was no correlation between BMI and risk of venous thromboembolism, tibiofemoral instability, or need for knee manipulation. Conclusions: The rates of reoperation, implant revision or removal, and many common complications after total knee arthroplasty were strongly associated with BMI. Level of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Objectives/HypothesisTo evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival.Study DesignRetrospective case series with chart review.MethodsThis study was conducted between 1998 and 2013 and included patients with HPV‐related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease‐specific survival (DSS). Secondary outcomes included overall survival (OS), disease‐free survival (DFS), adverse events, and gastrostomy tube rates.ResultsThirty‐nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow‐up was 39 months (range, 2–147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety‐two percent had extracapsular extension. Five‐year Kaplan‐Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%–99%), 87% (95% CI: 75%–99%), and 84% (95% CI: 72%–96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS.ConclusionsPatients with HPV‐related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long‐term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence.Level of Evidence4. Laryngoscope, 127:2033–2037, 2017

Abstract Serum levels of miR-194 have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion, and epithelial–mesenchymal transition in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR-194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo. Mechanistic investigations identified the ubiquitin ligase suppressor of cytokine signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194–driven metastatic phenotypes, whereas overexpression of a nontargetable SOCS2 reduced miR-194–stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacologic inhibition of ERK and JAK/STAT pathways reversed miR-194–driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer. Cancer Res; 77(4); 1021–34. ©2016 AACR.