The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

BACKGROUND: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. METHODS: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP-/-CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. RESULTS: WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP-/-aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. CONCLUSIONS: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

The Emerging Role of Histone Deacetylase Inhibitors in Cervical Cancer Therapy.

Cervical carcinoma is one of the most common cancers among women globally. Histone deacetylase inhibitors (HDACIs) constitute anticancer drugs that, by increasing the histone acetylation level in various cell types, induce differentiation, cell cycle arrest, and apoptosis. The aim of the current review is to study the role of HDACIs in the treatment of cervical cancer. A literature review was conducted using the MEDLINE and LIVIVO databases with a view to identifying relevant studies. By employing the search terms "histone deacetylase" and "cervical cancer", we managed to identify 95 studies published between 2001 and 2023. The present work embodies the most up-to-date, comprehensive review of the literature centering on the particular role of HDACIs as treatment agents for cervical cancer. Both well-established and novel HDACIs seem to represent modern, efficacious anticancer drugs, which, alone or in combination with other treatments, may successfully inhibit cervical cancer cell growth, induce cell cycle arrest, and provoke apoptosis. In summary, histone deacetylases seem to represent promising future treatment targets in cervical cancer.

Individual immune cell and cytokine profiles determine platelet-rich plasma composition.

OBJECTIVE: Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. DESIGN: For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. RESULTS: All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. CONCLUSIONS: Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual's immune profile and the concentration method appear to impact the final PRP product. TRIAL REGISTRATION: This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

Splenic artery steal syndrome in patients with orthotopic liver transplant: Where to embolize the splenic artery?

PURPOSE: This study compared proximal and distal embolization of the splenic artery (SA) in patients with splenic artery steal syndrome (SAS) after orthotopic liver transplantation (OLT) regarding post interventional changes of liver function to identify an ideal location of embolization. METHODS AND MATERIALS: 85 patients with SAS after OLT treated with embolization of the SA between 2007 and 2017 were retrospectively reviewed. Periinterventional DSA was used to assess treatment success and to stratify patients according to the site of embolization. Liver function was assessed using following laboratory values: bilirubin, albumin, gamma-glutamyl transferase, glutamat-pyruvat-transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), Alkaline Phosphatase (ALP), aPTT, prothrombin time and thrombocyte count. Descriptive statistics were used to summarize the data. Median laboratory values of pre, 1- and 3-days, as well as 1-week and 1-month post-embolization were compared between the respective embolization sites using linear mixed model regression analysis. RESULTS: All procedures were technically successful and showed an improved blood flow in the hepatic artery post-embolization. Ten Patients were excluded due to re -intervention or inconsistent image documentation. Pairwise comparison using linear mixed model regression analysis showed a significant difference between proximal and distal embolization for GPT (57.0 (IQR 107.5) vs. 118.0 (IQR 254.0) U/l, p = 0.002) and GOT (48.0 (IQR 48.0) vs. 81.0 (IQR 115.0) U/l, p = 0.008) 3-days after embolization as well as median thrombocyte counts 7-days after embolization (122 (IQR 108) vs. 83 (IQR 74) in thousands, p = 0.014). For all other laboratory values, no statistically significant difference could be shown with respect to the embolization site. CONCLUSION: We conclude that long-term outcomes after embolization of the SA in the scenario of SAS after OLT are irrespective of the site of embolization of the SA, whereas a proximal embolization potentially facilitates earlier normalization of liver function. Choice of technique should therefore be informed by anatomical conditions, safety considerations and preferences of the interventionalist.

Intramuscular and intratendinous placenta-derived mesenchymal stromal-like cell treatment of a chronic quadriceps tendon rupture.

BACKGROUND: Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long-term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro-angiogenic and immunomodulatory properties of placenta-derived adherent mesenchymal stromal-like (PLX-PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX-PAD cells in repetitively damaged tendon tissue. CASE: We report the case of an 80-year-old male patient with a chronic three-time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX-PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120° knee extension-flexion were observed at the 12 month follow-up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre-surgery: 0.98 m/s, 40 cm, 42.4 ± 12.4 N; 9 months post-surgery: 1.07 m/s, 0 cm, 10.4 ± 18.9 N) as well as hyperextension throughout stance and late swing phases (pre-surgery: -11.2 ± 0.9°; 9 months post-surgery: -2.7 ± 1.6°). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short-term immunoregulatory reaction with postoperatively increased interleukin (IL)-6 (pre-surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL-10 (pre-surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. CONCLUSIONS: Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add-on treatment with PLX-PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX-PAD cell treatment for tendon injuries.

Impact of the COVID-19 shutdown on orthopedic trauma numbers and patterns in an academic Level I Trauma Center in Berlin, Germany.

BACKGROUND: The COVID-19 pandemic led to the implementation of drastic shutdown measures worldwide. While quarantine, self-isolation and shutdown laws helped to effectively contain and control the spread of SARS-CoV-2, the impact of COVID-19 shutdowns on trauma care in emergency departments (EDs) remains elusive. METHODS: All ED patient records from the 35-day COVID-19 shutdown (SHUTDOWN) period were retrospectively compared to a calendar-matched control period in 2019 (CTRL) as well as to a pre (PRE)- and post (POST)-shutdown period in an academic Level I Trauma Center in Berlin, Germany. Total patient and orthopedic trauma cases and contacts as well as trauma causes and injury patterns were evaluated during respective periods regarding absolute numbers, incidence rate ratios (IRRs) and risk ratios (RRs). FINDINGS: Daily total patient cases (SHUTDOWN vs. CTRL, 106.94 vs. 167.54) and orthopedic trauma cases (SHUTDOWN vs. CTRL, 30.91 vs. 52.06) decreased during the SHUTDOWN compared to the CTRL period with IRRs of 0.64 and 0.59. While absolute numbers decreased for most trauma causes during the SHUTDOWN period, we observed increased incidence proportions of household injuries and bicycle accidents with RRs of 1.31 and 1.68 respectively. An RR of 2.41 was observed for injuries due to domestic violence. We further recorded increased incidence proportions of acute and regular substance abuse during the SHUTDOWN period with RRs of 1.63 and 3.22, respectively. CONCLUSIONS: While we observed a relevant decrease in total patient cases, relative proportions of specific trauma causes and injury patterns increased during the COVID-19 shutdown in Berlin, Germany. As government programs offered prompt financial aid during the pandemic to individuals and businesses, additional social support may be considered for vulnerable domestic environments.

3D Quantitative tumour burden analysis in patients with hepatocellular carcinoma before TACE: comparing single-lesion vs. multi-lesion imaging biomarkers as predictors of patient survival.

OBJECTIVES: To compare the ability of single- vs. multi-lesion assessment on baseline MRI using 1D- and 3D-based measurements to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) before transarterial chemoembolization (TACE). METHODS: This retrospective analysis included 122 patients. A quantitative 3D analysis was performed on baseline MRI to calculate enhancing tumour volume (ETV [cm(3)]) and enhancing tumour burden (ETB [%]) (ratio between ETV [cm(3)] and liver volume). Furthermore, enhancing and overall tumour diameters were measured. Patients were stratified into two groups using thresholds derived from the BCLC staging system. Statistical analysis included Kaplan-Meier plots, uni- and multivariate cox proportional hazard ratios (HR) and concordances. RESULTS: All methods achieved good separation of the survival curves (p < 0.05). Multivariate analysis showed an HR of 5.2 (95 % CI 3.1-8.8, p < 0.001) for ETV [cm(3)] and HR 6.6 (95 % CI 3.7-11.5, p < 0.001) for ETB [%] vs. HR 2.6 (95 % CI 1.2-5.6, p = 0.012) for overall diameter and HR 3.0 (95 % CI 1.5-6.3, p = 0.003) for enhancing diameter. Concordances were highest for ETB [%], with no added predictive power for multi-lesion assessment (difference between concordances not significant). CONCLUSION: 3D quantitative assessment is a stronger predictor of survival as compared to diameter-based measurements. Assessing multiple lesions provides no substantial improvement in predicting OS than evaluating the dominant lesion alone. KEY POINTS: • 3D quantitative tumour assessment on baseline MRI predicts survival in HCC patients. • 3D quantitative tumour assessment predicts survival better than any current radiological method. • Multiple lesion assessment provides no improvement than evaluating the dominant lesion alone. • Measuring enhancing tumour volume in proportion to liver volume reflects tumour burden.