In Vitro Characterization of a Tissue Renin-Angiotensin System in Human Nucleus Pulposus Cells.

Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from four human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter, the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 h of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Furthermore, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated by utilizing Western blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL-10, IL-8/IL-10, and TNF-α/IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease.

The use of negative pressure wound therapy for fracture-related infections following internal osteosynthesis of the extremity: A systematic review.

This study aimed to systematically review the current literature on studies using negative pressure wound therapy (NPWT) or dressings following fracture-related infection (FRI) in internal osteosynthesis of the extremity. Articles were analyzed on fracture and wound healing and included when comparing or describing the use of either NPWT or dressings in FRI. We conducted a systematic literature search in four electronic databases: Embase, Medline, the Cochrane Library, and Scopus. The studies were screened by two authors using Covidence.org and evaluated for risk of bias. A total of 8576 records were identified. No articles compared NPWT to dressings. Seven case reports and three case series included a total of 115 patients treated for FRI. Fracture healing was achieved in 21 out of 67 patients treated with NPWT (4 amputations and 46 not described) and all 48 patients in the dressing group (4 patients needed additional sequestrectomy procedures). Five studies did not describe fracture healing. In 57 out of 67 patients treated with NPWT, the wounds were described as healed, closed, or requiring soft tissue reconstruction (4 amputations and six lacking description). The dressing group had complete wound coverage in 18 patients and partial coverage in 30 patients. Studies were generally at high risk of bias because of insufficient descriptions of both patient demographics and outcomes. No studies compared NPWT to dressings, and the existing literature is at high risk of bias. The included studies were of low-level evidence. NPWT can be neither recommended nor advised against to cover infected osteosynthesis.

Elevation of Pro-Inflammatory Cytokine Levels Following Intra-Articular Fractures-A Systematic Review.

Introduction: Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by an elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. Methods: We searched Medline, Embase, and Cochrane databases (1960-February 2020) and included studies that were performed on human participants, and we included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle-Ottawa Scale. Results: Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukins (IL)-1ß, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to the control groups. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. Conclusions: Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.

The ability of comorbidity indices to predict mortality in an orthopedic setting: a systematic review.

BACKGROUND: Several comorbidity indices have been created to estimate and adjust for the burden of comorbidity. The objective of this systematic review was to evaluate and compare the ability of different comorbidity indices to predict mortality in an orthopedic setting. METHODS: A systematic search was conducted in Embase, MEDLINE, and Cochrane Library. The search were constructed around two primary focal points: a comorbidity index and orthopedics. The last search were performed on 13 June 2019. Eligibility criteria were participants with orthopedic conditions or who underwent an orthopedic procedure, a comparison between comorbidity indices that used administrative data, and reported mortality as outcome. Two independent reviewers screened the studies using Covidence. The area under the curve (AUC) was chosen as the primary effect estimate. RESULTS: Of the 5338 studies identified, 16 met the eligibility criteria. The predictive ability of the different comorbidity indices ranged from poor (AUC < 0.70) to excellent (AUC ≥ 0.90). The majority of the included studies compared the Elixhauser Comorbidity Index (ECI) and the Charlson Comorbidity Index (CCI). In-hospital mortality was reported in eight studies reporting AUC values ranging from 0.70 to 0.92 for ECI and 0.68 to 0.89 for CCI. AUC values were generally lower for all other time points ranging from 0.67 to 0.78. For 1-year mortality the overall effect size ranging from 0.67 to 0.77 for ECI and 0.69 to 0.77 for CCI. CONCLUSION: The results of this review indicate that the ECI and CCI can equally be used to adjust for comorbidities when analyzing mortality in an orthopedic setting. TRIAL REGISTRATION: The protocol for this systematic review was registered on PROSPERO, the International Prospective Register of Systematic Reviews on 13 June 2019 and can be accessed through record ID 133,871.

Operative versus nonoperative treatment of humeral shaft fractures: a systematic review and meta-analysis.

BACKGROUND: The humeral shaft fracture accounts for 1%-3% of all fractures and occurs in both the young and old population. However, the optimal treatment is still a matter of debate. Even though nonoperative treatment is commonly considered the gold standard, advantages have been described using operative stabilization. This systematic review aims to compare operative and nonoperative treatment in adult patients with humeral shaft fractures. METHOD: We used the following databases: PubMed, Embase, Cochrane, and CINAHL on October 1, 2018, searching for randomized controlled trials (RCTs) and cohort studies. Two reviewers screened the studies using Covidence, followed by systematic data extraction. The primary outcome was defined as posttreatment complications such as nonunion, radial nerve palsy, malunion, and infections. The secondary outcomes were functional scores and patient-reported outcome measures (PROMs). To assess study quality, the risk of bias in nonrandomized studies of interventions and the Cochrane risk of bias tool were used. RESULTS: Twelve studies were included: 1 RCT, 1 prospective cohort, and 10 retrospective cohorts with a total of 1406 patients, of whom 835 were treated operatively and 571 nonoperatively. Mean age ranged from 35 to 64, and 54% of the patients were male. The cohort studies had, in general, moderate bias, whereas the RCT had a low bias. There were statistically significant fewer nonunions in the operative treated group with a risk ratio of 0.49 (0.35-0.67), yielding a number needed to treat = 12. There were more deep infections in the operative group with a risk ratio of 2.76 (1.01-7.53) but otherwise no statistical differences concerning malunion or nerve damage. Only 1 study included PROM data. CONCLUSION: There were fewer nonunions in the operative group but more deep infections. Because of the lack of studies reporting PROMs, the potential positive effect of operative therapy in early aftercare could not be evaluated. Therefore, PROMs should be mandatory in future comparative studies.

The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.