Harnessing immunomodulation to combat sarcopenia: current insights and possible approaches.

Sarcopenia is a complex age-associated syndrome of progressive loss of muscle mass and strength. Although this condition is influenced by many factors, age-related changes in immune function including immune cell dynamics, and chronic inflammation contribute to its progression. The complex interplay between the immune system, gut-muscle axis, and autophagy further underscores their important roles in sarcopenia pathogenesis. Immunomodulation has emerged as a promising strategy to counteract sarcopenia. Traditional management approaches to treat sarcopenia including physical exercise and nutritional supplementation, and the emerging technologies of biophysical stimulation demonstrated the importance of immunomodulation and regulation of macrophages and T cells and reduction of chronic inflammation. Treatments to alleviate low-grade inflammation in older adults by modulating gut microbial composition and diversity further combat sarcopenia. Furthermore, some pharmacological interventions, nano-medicine, and cell therapies targeting muscle, gut microbiota, or autophagy present additional avenues for immunomodulation in sarcopenia. This narrative review explores the immunological underpinnings of sarcopenia, elucidating the relationship between the immune system and muscle during ageing. Additionally, the review discusses new areas such as the gut-muscle axis and autophagy, which bridge immune system function and muscle health. Insights into current and potential approaches for sarcopenia management through modulation of the immune system are provided, along with suggestions for future research directions and therapeutic strategies. We aim to guide further investigation into clinical immunological biomarkers and identify indicators for sarcopenia diagnosis and potential treatment targets to combat this condition. We also aim to draw attention to the importance of considering immunomodulation in the clinical management of sarcopenia.

Sarcopenia and Ageing.

Musculoskeletal ageing is a major health challenge as muscles and bones constitute around 55-60% of body weight. Ageing muscles will result in sarcopenia that is characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes. In recent years, a few consensus panels provide new definitions for sarcopenia. It was officially recognized as a disease in 2016 with an ICD-10-CM disease code, M62.84, in the International Classification of Diseases (ICD). With the new definitions, there are many studies emerging to investigate the pathogenesis of sarcopenia, exploring new interventions to treat sarcopenia and evaluating the efficacy of combination treatments for sarcopenia. The scope of this chapter is to summarize and appraise the evidence in terms of (1) clinical signs, symptoms, screening, and diagnosis, (2) pathogenesis of sarcopenia with emphasis on mitochondrial dysfunction, intramuscular fat infiltration and neuromuscular junction deterioration, and (3) current treatments with regard to physical exercises and nutritional supplement.

The imminent risk of a fracture-existing worldwide data: a systematic review and meta-analysis.

The overall incidence of imminent fracture after a prior fragility fracture was 7.58% in the first year and 11.58% in the first 2 years. Approximately half of re-fractures occurred in the first 2 years after a fragility fracture. Older patients that have suffered from a fragility fracture should be treated promptly, with immediate care and a secondary fracture prevention to prevent the high imminent risk of a fracture. INTRODUCTION: Imminent fractures refer to the fractures that occur within 2 years of an initial fracture. It is well known that the risk of a subsequent fracture is not constant with time and occurs shortly after the initial one. This systematic review and meta-analysis aimed to present the existing data on imminent fracture worldwide. METHODS: Literature search was conducted in Pubmed, Embase, and Web of Science databases until 26 October 2021 for studies reporting the incidence of imminent osteoporotic fractures among people aged 50 years or older. The overall incidence of imminent fracture was pooled and subgroup analyses of index fracture sites and regions on incidence of imminent fracture were performed, with the 95% confidence interval (CI) being calculated. Percentage of imminent fracture occurring in follow-up period was calculated and pooled by meta-analysis. Hazard ratio (HR) was used to estimate the gender differences on the imminent risk of fracture. RESULTS: A total of 1446 articles were identified. Nineteen observational studies were eligible for our systematic review, in which 18 were used for quantitative analysis. Pooled overall incidence of imminent fracture in the first year after an osteoporotic fracture was 7.58% (95% CI 5.84 to 9.31%) and cumulative incidence in the first 2 years was 11.58% (95% CI 8.94 to 14.21%). Subgroup analysis showed that in the first 2 years, the pooled incidence in Asia was 7.30% (95% CI 3.42 to 11.18%), whilst incidence in Europe/North America was 13.17% (95% CI 10.14 to 16.20%). In included studies with follow-up period of more than 5 years, pooled imminent fracture percentage in the first 2 years was 47.24% (95% CI 26.18 to 68.30%). Hazard ratio (HR) on gender showed that women had an overall slight increase in risk of imminent fractures (HR 1.18, 95% CI 1.11 to 1.25). CONCLUSION: The incidence of imminent fracture is high globally at 11.58%. Approximately half of all refractures occur in the first 2 years after an index fragility fracture. Older patients that have suffered from a fragility fracture should be treated promptly. Also, immediate care and secondary fracture prevention are necessary to prevent the high imminent risk of a fracture, especially within the first 2 years.

Low-Intensity Pulsed Ultrasound Stimulation for Bone Fractures Healing: A Review.

Low-intensity pulsed ultrasound (LIPUS) is a developing technology, which has been proven to improve fracture healing process with minimal thermal effects. This noninvasive treatment accelerates bone formation through various molecular, biological, and biomechanical interactions with tissues and cells. Although LIPUS treatment has shown beneficial effects on different bone fracture locations, only very few studies have examined its effects on deeper bones. This study provides an overview on therapeutic ultrasound for fractured bones, possible mechanisms of action, clinical evidences, current limitations, and its future prospects.

Open conversion with Crawford extent 3 thoracoabdominal aortic replacement after candy-plug implantation.

A patient who underwent candy-plug insertion in the year 2016 developed type 1B endoleak with rapid enlargement of distal descending thoracic aortic aneurysm in the year 2021 despite the initial successful false lumen occlusion and thrombosis. Open conversion with Crawford extent 3 thoracoabdominal aortic replacement was performed successfully and the patient was discharged home without any major complications.

Midterm clinical outcome of a case of aortic arch aneurysm treated with a novel arch stentgraft system.

INTRODUCTION: Open surgery is the gold standard treatment for aortic arch disease. However, due to its complexity, open arch replacement is associated with considerable risk of mortality and morbidity. METHOD: We report a case of a 71-year-old gentleman with multiple comorbidities and symptomatic 7 cm aortic arch aneurysm who was treated with a single-stage carotid-carotid and left carotid-axillary bypass followed by zone 0 aortic arch stenting with bimodular Nexus™ stent graft. RESULTS: Post-operatively, the patient suffered from a minor stroke with full neurological recovery. Follow-up computed tomography of the aorta 3 years post-stenting showed excellent stent position with no endoleak and complete resolution of the saccular aneurysm. DISCUSSION: The midterm result of our patient who was successfully treated with an off-the-shelf single branch, bimodular stent graft system is excellent with complete resolution of the arch saccular aneurysm at 3-year after the operation.

Retrospective record review on timing of COVID-19 vaccination and cardiac surgery.

BACKGROUND: Novel clinical challenges are faced by cardiac surgeons under the coronavirus disease 2019 (COVID-19) pandemic. Amidst the uncertainties faced due to the socioeconomic and public health impact, there is little evidence surrounding COVID-19 vaccination in patients undergoing cardiac surgery. Timing of vaccination and postvaccination adverse effects are required parameters to discuss with cardiac surgical patients. METHODS: This is a single-center, retrospective observational study. All patients who underwent adult cardiac surgery at the Prince of Wales Hospital, Hong Kong from January 2021 to December 2021 were included. Postoperative clinical outcomes, COVID-19 vaccination status, and vaccination-related adverse effects were collected. RESULTS: A total of 426 patients; 117 (27%) underwent isolated coronary artery bypass grafting, 111 (26%) underwent valvular surgery, and 97 (23%) underwent aortic surgery. Patients received either Sinovac CoronaVac or Pfizer BNT162b2 vaccine. Overall vaccination rate with at least 1 dose was 52% (n = 212), 15% (n = 63) received the first dose before surgery, 36% (n = 149) received the first dose vaccination after surgery. Rate of completion with second and third doses of vaccination were 22% (n = 89) and 4.9% (n = 20), respectively. The mean timing of first dose of vaccine after surgery was 216 ± 84 days from operation. Three (1.4%) patients recorded vaccination-related complications. CONCLUSIONS: COVID-19 vaccination is safe in patients who received major cardiac surgery, with low adverse effects recorded and no vaccine-related mortality observed. A time frame of 3-6 months after cardiac surgery receiving COVID-19 vaccination is reasonable and could serve as a guidance for future COVID-19 vaccination booster programs.

Coapplication of Magnesium Supplementation and Vibration Modulate Macrophage Polarization to Attenuate Sarcopenic Muscle Atrophy through PI3K/Akt/mTOR Signaling Pathway.

Sarcopenia is an age-related geriatric syndrome characterized by the gradual loss of muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to be beneficial to structural and functional outcomes of skeletal muscles, while magnesium (Mg) is a cofactor associated with better indices of skeletal muscle mass and strength. We hypothesized that LMHFV, Mg and their combinations could suppress inflammation and sarcopenic atrophy, promote myogenesis via PI3k/Akt/mTOR pathway in senescence-accelerated mouse P8 (SAMP8) mice and C2C12 myoblasts. Results showed that Mg treatment and LMHFV could significantly decrease inflammatory expression (C/EBPα and LYVE1) and modulate a CD206-positive M2 macrophage population at month four. Mg treatment also showed significant inhibitory effects on FOXO3, MuRF1 and MAFbx mRNA expression. Coapplication showed a synergistic effect on suppression of type I fiber atrophy, with significantly higher IGF-1, MyoD, MyoG mRNA (p < 0.05) and pAkt protein expression (p < 0.0001) during sarcopenia. In vitro inhibition of PI3K/Akt and mTOR abolished the enhancement effects on myotube formation and inhibited MRF mRNA and p85, Akt, pAkt and mTOR protein expressions. The present study demonstrated that the PI3K/Akt/mTOR pathway is the predominant regulatory mechanism through which LMHFV and Mg enhanced muscle regeneration and suppressed atrogene upregulation.

Can we enhance osteoporotic metaphyseal fracture healing through enhancing ultrastructural and functional changes of osteocytes in cortical bone with low-magnitude high-frequency vibration?

Fragility fractures are related to the loss of bone integrity and deteriorated morphology of osteocytes. Our previous studies have reported that low-magnitude high-frequency vibration (LMHFV) promoted osteoporotic fracture healing. As osteocytes are known for mechanosensing and initiating bone repair, we hypothesized that LMHFV could enhance osteoporotic fracture healing through enhancing morphological changes in the osteocyte lacuna-canalicular network (LCN) and mineralization. A metaphyseal fracture model was established in female Sprague-Dawley rats to investigate changes in osteocytes and healing outcomes from early to late phase post-fracture. Our results showed that the LCN exhibited an exuberant outgrowth of canaliculi in the osteoporotic fractured bone at day 14 after LMHFV. LMHFV upregulated the E11, dentin matrix protein 1 (DMP1), and fibroblast growth factor 23 (FGF23), but downregulated sclerostin (Sost) in osteocytes. Moreover, LMHFV promoted mineralization with significant enhancements of Ca/P ratio, mineral apposition rate (MAR), mineralizing surface (MS/BS), and bone mineral density (BMD) in the osteoporotic group. Consistently, better healing was confirmed by microarchitecture and mechanical properties, whereas the enhancement in osteoporotic group was comparable or even greater than the normal group. This is the first report to reveal the enhancement effect of LMHFV on the osteocytes' morphology and functions in osteoporotic fracture healing.

Hepatorenal dysfunction predicts operative mortality after triple valve surgery: Utility of MELD-Na.

BACKGROUND: Despite significant advancements in operative techniques and myocardial protection, triple valve surgery (TVS) remains a formidable operation with a relatively high in-hospital mortality. We evaluated the prognostic value of Model for End-stage Liver Disease score including sodium (MELD-Na) for mortality after TVS and its predictive value when incorporated in the EuroSCORE risk model. METHODS: We performed a retrospective cohort study of 61 consecutive patients who underwent TVS from November 2005 to June 2016. Demographics, clinical, biochemical, and operative data were collected and analyzed. RESULTS: Median follow-up duration was 8.0 years. The majority (70.5%) of patients suffered from rheumatic heart disease and underwent mechanical double valve replacement with tricuspid valve repair. There were six operative deaths (9.84%), with the most common cause of death being multiorgan failure (83.3%). In 26.2% of the cohort, the MELD-Na score was moderately elevated at 9 to 15. A small fraction (4.9%) had a severely elevated MELD-Na greater than 15. Patients with a MELD-Na greater than 9 had a higher unadjusted rate of operative mortality, prolonged ventilation, need for dialysis and acute liver failure after TVS. Hierarchical logistic regression was performed using logistic EuroSCORE as the base model. After risk adjustment, each point of MELD-Na score increase was associated with 1.405 times increase in odds of operative mortality. The regression analysis was repeated by incorporating individual components of the MELD-Na score, including bilirubin, sodium, and albumin. All three biochemical parameters were significantly associated with operative mortality CONCLUSION: MELD-Na score as a quantifier of hepatorenal dysfunction is sensitive and specific for operative mortality after triple valve surgery.

Valiant NAVION stent graft system application: First Asian case-series analysis.

BACKGROUND AND AIM: The Valiant NavionTM stent graft system is a third-generation low profile thoracic endograft designed for thoracic endovascular aortic repair. In this population analysis, we report on the first Asian all-comers experience and outcomes who underwent thoracic endovascular aortic repair with the use of this new stent graft system. METHODS: Between May 2019 and October 2020, 21 patients with different aortic pathologies were prospectively recruited and retrospectively analyzed. Important clinical and device-related outcomes were evaluated. The endpoints included short-term survival, technical success, access failures, major vascular and clinical complications, endoleaks, and hospital stay. RESULTS: The commonest indication of stenting was penetrating aortic ulcers (28.6%) and six (28.6%) patients had emergency stenting performed for aortic transection or rupture. 30 days of survival postprocedure was recorded and complete. There were no major vascular complications. Deployment accuracy was 100%, and the technical success rate was 94.7% (18/19) with one patient having a Type 2 endoleak on follow-up imaging. No neurological complications were noted. The mean operative time was 95 ± 73.6 min and the mean fluoroscopy time was 16.2 ± 10.8 min. Mean hospital stay for elective zone 2, 3, and 4 stenting was 5.3 ± 3.8 days, and only one patient postzone 1 thoracic endovascular aortic repair required a brief (0.5 days) ICU stay. All procedures were performed via the percutaneous transfemoral route with 100% success in percutaneous closure. CONCLUSION: This first reported Asian case series demonstrated versatility, safety, and efficacy of the Valiant NavionTM stent in Asian patients with different aortic pathologies.

Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway.

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition. We hypothesized that incubation of non-small cell lung cancer (NSCLC) cells with heat-inactivated Escherichia coli can augment cancer cell adhesion, migration and metastasis via TLR4 signaling. Incubation of murine and human NSCLC cells with E. coli increased in vitro cell adhesion to collagen I, collagen IV and fibronectin, and enhanced in vitro migration. Using hepatic intravital microscopy, we demonstrated that NSCLC cells have increased in vivo adhesion to hepatic sinusoids after coincubation with gram negative bacteria. These enhanced cell adhesion and migration phenotypes following incubation with E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), p38 MAPK (BIRB0796) and ERK1/2 phosphorylation (PD184352). Incubation of murine NSCLC cells in vitro with E. coli prior to intrasplenic injection significantly augmented formation of in vivo hepatic metastases 2 weeks later. This increase was abrogated by NSCLC TLR4 blockade using Eritoran. TLR4 represents a potential therapeutic target to help prevent severe postoperative infection driven cancer metastasis.

A survey of perceived training differences between ophthalmology residents in Hong Kong and China.

BACKGROUND: To study the differences in ophthalmology resident training between China and the Hong Kong Special Administrative Region (HKSAR). METHODS: Training programs were selected from among the largest and best-known teaching hospitals. Ophthalmology residents were sent an anonymous 48-item questionnaire by mail. Work satisfaction, time allocation between training activities and volume of surgery performed were determined. RESULTS: 50/75 residents (66.7 %) from China and 20/26 (76.9 %) from HKSAR completed the survey. Age (28.9 ± 2.5 vs. 30.2 ± 2.9 years, p = 0.15) and number of years in training (3.4 ± 1.6 vs. 2.8 ± 1.5, p = 0.19) were comparable between groups. The number of cataract procedures performed by HKSAR trainees (extra-capsular, median 80.0, quartile range: 30.0, 100.0; phacoemulsification, median: 20.0, quartile range: 0.0, 100.0) exceeded that for Chinese residents (extra-capsular: median = 0, p < 0.0001; phacoemulsification: median = 0, p < 0.0001). Chinese trainees spent more time completing medical charts (>50 % of time on charts: 62.5 % versus 5.3 %, p < 0.0001) and received less supervision (≥90 % of training supervised: 4.4 % versus 65 %, p < 0.0001). Chinese residents were more likely to feel underpaid (96.0 % vs. 31.6 %, p < 0.0001) and hoped their children would not practice medicine (69.4 % vs. 5.0 %, p = 0.0001) compared HKSAR residents. CONCLUSIONS: In this study, ophthalmology residents in China report strikingly less surgical experience and supervision, and lower satisfaction than HKSAR residents. The HKSAR model of hands-on resident training might be useful in improving the low cataract surgical rate in China.

Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole.

Aromatase inhibitors (AIs) have been used as adjuvant therapeutic agents for breast cancer. Their adverse side effect on blood lipid is well documented. Some natural compounds have been shown to be potential AIs. In the present study, we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole (Femara; Novartis Pharmaceuticals, East Hanover, NJ) in a cell and a mouse model. In the in vitro experimental results for aromatase inhibition, the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM, respectively. Both letrozole and luteolin appeared to be competitive inhibitors. Subsequently, an animal model was used for the comparison. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. Luteolin was given by mouth at 5, 20, and 50 mg/kg, whereas letrozole was administered by intravenous injection. Similar to letrozole, luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation. The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL, cyclin-A/D1/E, CDK2/4, and increase in that of Bax-was about the same in both treatments. The most significant disparity was on blood lipids. In contrast to letrozole, luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile. These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs.

Callus formation is related to the expression ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic fracture healing.

INTRODUCTION: This study characterizes ovariectomized (OVX)-induced osteoporotic fracture healing with focus on estrogen receptors (ERs). Callus formation plays a critical role in fracture healing, and ERs are well-known mechanosensors in osteogenic pathways. It was hypothesized that callus formation was related to and partially determined by the difference in expression patterns of ERs in both normal and OVX-induced osteoporotic fractures. METHODS: Closed femoral fracture in SHAM and ovariectomized rats were used in this study. Weekly callus width (CW) and area (CA), endpoint mechanical properties, gene expressions of Col-1, BMP-2, ER-α, ER-ß and ER-α:ER-ß ratios (ER-ratios), and correlations were assessed at 2, 4 and 8 weeks post-fracture. RESULTS: CW and CA results confirmed that OVX-induced osteoporotic fracture was delayed at 2-4 weeks with impaired endpoint mechanical properties. Gene expressions of ER-α and ER-ß were higher in the SHAM group at week 2 (p < 0.05) and later lowered at week 8; whereas the OVX group showed an opposing trend. Moderate correlation existed between ER-α and BMP-2 (0.545, p = 0.003), and ER-ratio and BMP-2 (0.601, p = 0.001), and BMP-2 to CW and CA (r = 0.709, p = 0.000 and r = 0.588, p = 0.001, respectively). ER-α and ER-ß proteins expressions were confirmed by immunohistochemistry at the fracture callus in reparative progenitor cells, osteoblasts- and osteoclasts-like cells. CONCLUSION: We conclude that the delayed healing rate and impaired callus quality in OVX-induced osteoporotic fracture is related to the delayed expression of ERs. A high ER-α:ER-ß ratio favors callus formation.

Correction: Pius et al. Effects of Aging on Osteosynthesis at Bone-Implant Interfaces. Biomolecules 2024, 14, 52.

Max L. Lee was not included as an author in the original publication [...].

Individualized treatment of type A intramural hematoma-upfront surgery is not always necessary.

Background: Management of acute type A intramural hematoma (IMH) is a controversial topic, and variable treatment strategies have been reported. Upfront aortic replacement may not be necessary in all cases. The goal of our study was to evaluate clinical outcomes of patients with acute type A IMH or thrombosed false lumen (FL) treated with upfront surgery or watchful waiting. Methods: Patients admitted to our hospital with type A IMH or aortic dissection with thrombosed ascending FL from December 2012 to February 2023 were retrospectively reviewed. Results: Among the 93 patients with type A IMH, 36 (38.7%) patients underwent upfront aortic surgery (Group S), and 57 (61.3%) patients were offered watchful waiting with medical surveillance (Group W). Of the 57 patients in Group W, 32 were treated conservatively with medical therapy alone (Group C). Patients in Group S had larger ascending aortic diameter (47.8±5.3 vs. 44.4±4.2 mm: P=0.001), higher frequency of pericardial effusion (38.9% vs. 10.5%; P=0.001) and cardiac tamponade (16.7% vs. 1.8%; P=0.008). The overall mortality rate was 4.3% in the whole cohort over a median follow up of 40.5 months. Overall survival for Group S was 100% at 30 days and 1 year, and 96.2% at 5 years. Overall survival for Group W was 98.2% at 30 days, 96.3% at 1 year and 95.2% at 5 years. The difference in overall survival was not statistically significant (P=0.64). Overall survival for Group C was 100% at 30 days and 1 year, and 90.9% at 5 years. Conclusions: Survival outcomes in selected patients with type A IMH were satisfactory. An individualized approach to patients with uncomplicated type A IMH was feasible. Upfront surgery was not necessary in all cases.

Sex differences of NF-κB-targeted therapy for mitigating osteoporosis associated with chronic inflammation of bone.

Aims: Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice. Methods: We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR). Results: Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN. Conclusion: We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males.