New glycoconjugation strategies for Ruthenium(II) arene complexes via phosphane ligands and assessment of their antiproliferative activity.

Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEß and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1ß and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1ß and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2ß and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-ß-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3∙BH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4∙BH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3∙BH3 and 4∙BH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1ß, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the ß anomer. However, Ru1ß, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1ß, inducing cell death by apoptosis.

Balance Remains Impaired after Hip Arthroplasty: A Systematic Review and Best Evidence Synthesis.

BACKGROUND: Hip arthroplasty (HA) is the most common intervention for joint replacement, but there is no consensus in the literature on the real influence of this procedure on balance, or on what factors in the pre-operative, surgical, and post-operative stages may affect it. PURPOSE: To synthesize the evidence on how Hip Arthroplasty (HA) affects balance, identifying pre-operative, surgical, and postoperative risk factors that may impair balance in HA patients, with the aim to improve patients' management strategies. METHODS: A literature search was performed on PubMed, PeDRO, and Cochrane Collaboration on 25 May 2021. INCLUSION CRITERIA: clinical report of any level of evidence; written in English; with no time limitation; about balance changes in hip osteoarthritis (OA) patients undergoing HA and related factors. RESULTS: 27 papers (391 patients) were included. Overall, the evidence suggested that balance is impaired immediately after surgery and, 4-12 months after surgery, it becomes better than preoperatively, although without reaching the level of healthy subjects. A strong level of evidence was found for hip resurfacing resulting in better balance restoration than total HA (THA), and for strength and ROM exercises after surgery positively influencing balance. CONCLUSION: Both the surgical technique and the post-operative protocols are key factors influencing balance; thus, they should be carefully evaluated when managing hip OA in patients undergoing HA. Moreover, balance at 4-12 months after surgery is better than preoperatively, although without reaching the level of the healthy population. Attention should be paid in the early post-operative phase, when balance may be impaired in patients undergoing HA.

Comparison of the survivorship between arthroplasty and ORIF for basi-cervical femoral neck fractures in the overall population and in polymorbid patients.

BACKGROUND: Femoral neck fractures (FNFs) are associated with high mortality and can be treated with arthroplasty or open reduction and internal fixation (ORIF). For basi-cervical FNFs, there is no agreement on which procedure is better. Do arthroplasty and open reduction with internal fixation (ORIF) have different rates of survival? Do age and comorbidities influence survivorship? HYPOTHESIS: Patients who underwent arthroplasty and patients who underwent ORIF have different rates of survival. PATIENTS AND METHODS: Survivorship curves, complications, and hospitalisation length were analysed in 154 patients who received hip arthroplasty, and in 72 patients who received ORIF. Age and ASA score were used to divide the patients into sub-groups and perform secondary analyses. RESULTS: At 4.9±2.4 years after surgery, 74 patients in the arthroplasty group (48%) and 33 in the ORIF group (45%) had died. The survivorship curves of the two groups showed a non-significant difference. The hospitalisation length was 13.5±8.9 days, with a non-significant difference between groups. There were 130 complications in total: 97 in the arthroplasty patients (19 patients had multiple complications, 52 had only one), 33 in the ORIF patients (4 patients had multiple complications, 29 had only one); the odds ratio was therefore 2.1 (p=0.02). Age, ASA score, Sernbo score, Charlson comorbidity index, and sex (male) were the best predictors of mortality. In the ASA 3-4 sub-group, the survivorship curves showed a lower mortality in the arthroplasty group (p=0.02). DISCUSSION: Arthroplasty and ORIF are both valid procedures for the treatment of basi-cervical FNFs, but a high mortality rate is associated with either procedures. There is no difference in terms of survivorship between arthroplasty and ORIF in the overall population, but the presence of comorbidities may favour arthroplasty, which should be considered when managing patients with basi-cervical FNFs. LEVEL OF EVIDENCE: III; retrospective, observational study.

Outpatient total knee arthroplasty leads to a higher number of complications: a meta-analysis.

BACKGROUND: Careful pre- and post-operative management can allow surgeons to perform outpatient TKA, making this a more affordable procedure. The aim of the present meta-analysis is to compare outpatient and inpatient TKA. METHODS: A systematic search of the literature was performed in July 2020 on PubMed, Web of Science, Cochrane library, and on the grey literature databases. The papers collected were used for a meta-analysis comparing outpatient and inpatient TKA in terms of complication and readmission rates. Risk of bias and quality of evidence were defined according to Cochrane guidelines. RESULTS: The literature search resulted in 4107 articles; of these, 8 articles were used for the meta-analysis. A total of 212,632 patients were included, 6607 of whom were TKA outpatients. The overall complication rate for outpatient TKAs was 16.1%, while inpatient TKAs had an overall lower complication rate of 10.5% (p = 0.003). The readmission rate was 4.9% in outpatient TKAs and 5.9% in inpatient TKAs. Only 3 studies reported the number of deaths, which accounted for 0%. The included studies presented a moderate risk of bias, and according to GRADE guidelines, the level of evidence for complications and readmissions was very low. CONCLUSIONS: This meta-analysis documented that outpatient TKA led to an increased number of complications although there were no differences in the number of readmissions. However, future high-level studies are needed to confirm results and indications for the outpatient approach, since the studies currently available have a moderate risk of bias and a very low quality of evidence.

Bone Bruise and Anterior Cruciate Ligament Tears: Presence, Distribution Pattern, and Associated Lesions in the Pediatric Population.

BACKGROUND: Bone bruise characteristics after anterior cruciate ligament (ACL) injury have been correlated with the level of joint derangement in adults. However, the literature lacks information about younger patients, whose higher ligamentous laxity may lead to different lesion patterns. PURPOSE: To investigate the prevalence, size, location, and role of bone bruise associated with ACL rupture in the pediatric population. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Knee magnetic resonance imaging scans (MRIs) of patients aged 8 to 16 years with ACL tears from 2010 to 2018 were selected from the institution database. Inclusion criteria were open or partially open physes, less than 90 days between trauma and MRI, and no history of injury or surgery. Presence, localization, and size of bone bruise were analyzed by 2 blinded researchers and scored with the Whole-Organ Magnetic Resonance Imaging Score (WORMS) bone bruise subscale. Ligamentous, cartilaginous, meniscal, and other lesions were documented. RESULTS: Of the 78 pediatric patients selected from the database, 54 (69%) had bone bruise. The mean area of bone bruise was larger in males than in females (femur, 3.8 ± 2.8 vs 2.2 ± 1.4 cm2, respectively, P = .006; tibia, 2.6 ± 1.6 vs 1.5 ± 0.8 cm2, respectively, P = .007). The subregions most affected by bone bruise were the lateral posterior tibia and the lateral central femur (in 83% and 80% of the knees affected, respectively). A low correlation was found between age and bone bruise area (biggest areas r = 0.30, P = .03, and sum of areas r = 0.27, P = .04), but no correlation was found between age and WORMS (femur, r = -0.03, P = .85; tibia, r = -0.04, P = .76). The injuries most associated with bone bruise were 23 meniscal lesions (43%), 10 lesions of other ligaments (19.0%), 2 cartilage lesions (3.7%), and 2 patellar fractures (3.7%). CONCLUSION: The prevalence of bone bruises in pediatric patients with ACL tears is high, although it seems slightly lower than the prevalence documented in adults but with similar localization. The area and the distribution pattern of bone bruises are similar among different ages. The pediatric patients had a lower presence of cartilage and meniscal lesions compared with that reported in adults, which suggests a different effect of this trauma on the knee of pediatric patients.

4-Aryliden-2-methyloxazol-5(4H)-one as a new scaffold for selective reversible MAGL inhibitors.

This study reports on a preliminary structure-activity relationship exploration of 4-aryliden-2-methyloxazol-5(4H)-one-based compounds as MAGL/FAAH inhibitors. Our results highlight that this scaffold may serve for the development of selective MAGL inhibitors. A 69-fold selectivity against MAGL over FAAH was achieved for compound 16b (MAGL and FAAH IC(50) = 1.6 and 111 µM, respectively). Furthermore, the best compound behaved as a reversible ligand and showed promising antiproliferative activity in cancer cells.