Redox Dysregulation of Vascular Smooth Muscle Sirtuin-1 in Thoracic Aortic Aneurysm in Marfan Syndrome.

BACKGROUND: Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases). METHODS: In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1mgR/mgR), an established model of Marfan syndrome prone to aortic dissection/rupture. RESULTS: Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1mgR/mgR mice, before induction of severe oxidative stress markers. Fbn1mgR/mgR aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFß (transforming growth factor beta), which was increased in Fbn1mgR/mgR aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell-specific deletion of SirT1 in Fbn1mgR/mgR mice (SMKO-Fbn1mgR/mgR) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1mgR/mgR mice, compared with 25% of Fbn1mgR/mgR mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells. CONCLUSIONS: Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA and TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed.

Meniscal Injuries in Patients Aged 40 Years or Older: A Comparative Study Between Meniscal Repair and Partial Meniscectomy.

Introduction Meniscal tears represent one of the most frequent knee injuries and are the most common cause of knee surgery. Historically, age has been considered an independent factor contraindicating meniscal repair due to the assumption that meniscal injuries in this population are frequently chronic tears, mostly with a degenerative tear pattern, and low healing potential. However, recent literature has questioned this paradigm with studies reporting successful outcomes with meniscal repair in older patients. Our study aimed to evaluate and compare the short-term clinical outcomes of meniscal repair versus partial meniscectomy in patients aged ≥40 years old. Methods A retrospective study was conducted that included patients over the age of 40 years, diagnosed with meniscal tears, that underwent arthroscopically assisted meniscal repair or partial meniscectomy between 01 January and 31 December 2020. The patients were divided into two groups: Group 1- partial meniscectomy (PM) and Group 2- meniscal repair (MR). The clinical evaluation was performed 24 months after the surgery, and the studied variables were: function (Tegner Lysholm Knee Scoring Scale), pain (Visual Analogue Scale), patient satisfaction, and failure rate.  Results Fifty-one patients met the inclusion criteria, and 7 were excluded due to loss of follow-up during telephone contact. Thus, the final sample consisted of 44 patients (mean age 52.18y), both groups with 22 patients. In both groups, we found an improvement in pain 2 years after the surgery, with a decrease in the VAS value between the pre and post-surgery. On average, the VAS score decreased from 7.9 to 4.5 in the group subjected to partial meniscectomy, and from 7.5 to 3.2 in the meniscal repair. This was statistically significant in both groups, with a p-value <0.01, but not between them (p-value = 0.363). Comparing the degree of satisfaction between both groups, we found no statistically significant difference between them (p=0.167). Regarding the functional outcome (Tegner Lysholm Knee Scoring Scale), the group that underwent the meniscal repair obtained a statistically superior score compared to the partial meniscectomy group (77.55 vs. 64.77; p-value 0.033). The failure rate was exactly equal in both groups (4.5%), therefore no statistically significant difference was found in this variable.  Conclusion Age, as an independent factor, should not be considered a contraindication for meniscus repair. In fact, if technically possible, meniscal repair should always be performed as it is associated with better functional outcomes, similar failure rates, and may be protective against the development and progression of arthritis.

Are professional handball players at risk for developing a glenohumeral internal rotation deficit in their dominant arm?

OBJECTIVES: Overhead athletes, such as baseball players, have been shown to have adaptive changes in the shoulder range of motion (ROM) of their dominant arm. Professional handball players are a unique subtype of overhead athletes with very different demands from baseball players. The aim of this study was to determine if professional handball players demonstrate differences in shoulder ROM between their dominant and non-dominant arm and try to relate them with new variables. METHODS: Fifty professional male handball players were included and completed a questionnaire regarding age at which they started to play, number of hours they practice a week, field position and arm dominance. ROM measurements were performed including forward flexion (FF), external rotation with the shoulder in abduction (ABER) and with adducted arm (ADER) and internal rotation with shoulder in abduction (IR). Statistical analysis was performed to determine differences in ROM between the dominant and non-dominant shoulder and if there is a relationship between these differences and shoulder load or field position. RESULTS: The dominant arm showed decreased internal rotation (47 vs. 56 degrees, p < 0.001) and increased external rotation both with the arm abducted (99 vs. 88 degrees, p < 0.001) and at the side (62 vs 57 degrees, p = 0.001). This was not correlated with shoulder load for any movement (FF, p = 0.980; ABER, p = 0.741; ADER, p = 0.803; IR, p = 0.085) but was dependent on field position with first line players showing the highest internal rotation deficit (13 degrees vs. 6-7 degrees in the other field positions, p = 0.013). CONCLUSION: This study showed that professional male handball players with a first line position have a significant risk for developing a glenohumeral internal rotation deficit, similar to the phenomenon seen in baseball pitchers.