Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease.

Chronic renal disease (CRD) accelerates the development of atherosclerosis. The potent protease cathepsin S cleaves elastin and generates bioactive elastin peptides, thus promoting vascular inflammation and calcification. We hypothesized that selective cathepsin S inhibition attenuates atherogenesis in hypercholesterolemic mice with CRD. CRD was induced by 5/6 nephrectomy in high-fat high-cholesterol fed apolipoprotein E-deficient mice. CRD mice received a diet admixed with 6.6 or 60 mg/kg of the potent and selective cathepsin S inhibitor RO5444101 or a control diet. CRD mice had significantly higher plasma levels of osteopontin, osteocalcin, and osteoprotegerin (204%, 148%, and 55%, respectively; P < 0.05), which were inhibited by RO5444101 (60%, 40%, and 36%, respectively; P < 0.05). Near-infrared fluorescence molecular imaging revealed a significant reduction in cathepsin activity in treated mice. RO5444101 decreased osteogenic activity. Histologic assessment in atherosclerotic plaque demonstrated that RO5444101 reduced immunoreactive cathepsin S (P < 0.05), elastin degradation (P = 0.01), plaque size (P = 0.01), macrophage accumulation (P < 0.01), growth differentiation factor-15 (P = 0.0001), and calcification (alkaline phosphatase activity, P < 0.01; osteocalcin, P < 0.05). Furthermore, cathepsin S inhibitor or siRNA significantly decreased expression of growth differentiation factor-15 and monocyte chemotactic protein-1 in a murine macrophage cell line and human primary macrophages. Systemic inhibition of cathepsin S attenuates the progression of atherosclerotic lesions in 5/6 nephrectomized mice, serving as a potential treatment for atherosclerosis in patients with CRD.

Cerebral Venous Thrombosis in Pregnant and Postpartum Women Presenting to the Emergency Department with Headaches.

Introduction: Cerebral venous thrombosis (CVT) is a thromboembolic disease of the intracranial venous systems. The disease can be difficult to diagnose as it often requires a high index of suspicion. Risk factors for the disease include pregnancy, oral contraceptive pills, congenital thrombophilia, infection, cancer, polycythemia, head trauma, and recent surgery. However, there have been no studies in the United States that have examined whether pregnancy and the postpartum stage are truly a risk factor for CVT. The aim of this study is to determine whether pregnant and postpartum women presenting to the emergency department with headaches have a higher incidence of CVT to better risk stratify which patients need to have advanced imaging pursued. Methods: A retrospective, observational case-control study was performing by querying the electronic medical record at a large county hospital for patients presenting with a headache to the emergency department. Patients were stratified into groups based on whether they were diagnosed with CVT, pregnancy status, and comorbid conditions to determine the risk associated between pregnancy, the puerperium stage, and CVT. Results: A total of 20,955 males and females presented to the emergency department between January 1, 2016 and April 13, 2023, with a chief complaint of headache. There were 19,474 female patients and 9581 male patients. In the case group, there were 793 pregnant women and 53 postpartum women. In the control group, there were 18,628 women who were not pregnant. Of the 22 patients diagnosed with CVT, 1 was in the puerperium stage and no patients were pregnant. Pregnant and postpartum patients were 1.05 (0.14-7.80) times more likely to develop CVT. Pregnant and postpartum patients were 1.73 (0.23-13.52) times more likely to develop CVT when controlled for comorbidities. Patients in the puerperium stage were 26.48 (3.33-210.87) times more likely to develop CVT when controlled for comorbidities. Conclusion: Pregnant patients presenting to the emergency department with headaches do not have a significantly higher risk of CVT; however, puerperium patients have a significantly higher risk of CVT compared to the general population.

Effects of Multibracket Orthodontic Treatment versus Clear Aligners on Periodontal Health: An Integrative Review.

Objective: This integrative review aimed to identify studies comparing the periodontal health in patients wearing multibracket orthodontic appliances and clear aligners. Materials and methods: An integrative literature search was performed through different databases, PubMed/Medline, PMC, and the Cochrane Library. This work was submitted to a search strategy following the PICO method and included the focus question: "Could the chosen orthodontic appliance change significantly the oral hygiene of the patient, impairing the periodontal health?" This work included analytical and controlled studies on humans published between 2005 and 2020, in the English language, establishing a comparison of the periodontal status in patients undergoing orthodontic multibracket and clear aligners therapies. The main periodontal indexes assessed were plaque index (PI), pocket depth (PD), gingival index (GI), and bleeding on probing (BoP). Results: The electronic research displayed 386 articles on PMC, 106 on PubMed, and 40 on the Cochrane Library. After removal, just 25 articles were selected for full-text screening, but just eight studies were eligible for this integrative review. It was enumerated that 204 patients were treated with aligners and 294 with multibracket orthodontic appliances, mainly elastomeric ligated brackets. Only the plaque index displayed a significant difference between the two groups and general data obtained showed a better control for periodontal health in the clear aligners. Limitations such as age, malocclusion severity, therapeutic choice, and different time measure was observed. In addition, the oral hygiene instruction and follow-up by a professional were different, and the role of malocclusion was not present in the studies. Conclusions: Within the limitations of this study, better results for periodontal health were found in the clear aligners. Therefore, more studies are necessary to affirm that aligners are synonymous with better gingival conditions in comparison with multibracket appliances. Other variables such as oral hygiene instructions, motivation, and supportive treatment tend to be more prevalent than the type of appliance itself in the periodontal evaluation.

Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling.

BACKGROUND: Ischemic mitral regurgitation (MR) is classically ascribed to functional restriction of normal leaflets, but recent studies have suggested post-myocardial infarction (MI) mitral valve (MV) leaflet fibrosis and thickening, challenging valve normality. Progression of leaflet thickness post-MI has not been studied. We hypothesized that excessive MV remodeling post-MI contributes to MR. Our objectives are to characterize MV changes after MI and relate them to MR. METHODS AND RESULTS: Three groups of 40 patients with serial echocardiograms over a mean of 23.4 months were identified from an echocardiography database: patients first studied early (6±12 days) and late (12±7 years) after an inferior MI and normal controls. MV thickness was correlated with MR. We studied the mechanisms for MV changes in a sheep model (6 apical MI versus 6 controls) followed for 8 weeks, with MV cellular and histopathologic analyses. Early post-MI, leaflet thickness was found to be similar to controls (2.6±0.5 vs 2.5±0.4 mm; P=0.23) but significantly increased over time (2.5±0.4 to 2.9±0.4 mm; P<0.01). In this group, patients tolerating maximal doses of renin-angiotensin blocking agents had less thickening (25% of patients; P<0.01). The late-MI group had increased thickness (3.2±0.5 vs 2.5±0.4 mm; P<0.01) without progression. At follow-up, 48% of post-MI patients had more than mild MR. Increased thickness was independently associated with MR. Experimentally, 8 weeks post-MI, MVs were 2-fold thicker than controls, with increased collagen, profibrotic transforming growth factor-ß, and endothelial-to-mesenchymal transformation, confirmed by flow cytometry. CONCLUSIONS: MV thickness increases post-MI and correlates with MR, suggesting an organic component to ischemic MR. MV fibrotic remodeling can indicate directions for future therapy.

National trends of psychotropic medication use among patients diagnosed with anxiety disorders: results from medical expenditure panel survey 2004-2009.

Data from the 2004 to 2009 Medical Expenditure Panel Survey (MEPS) were used to: (1) characterize changes in utilization and (2) identify factors associated with the use of psychotropic medication among patients with anxiety disorders. We calculated the prevalence, compared the use patterns for each year and drug class, and used logistic regression to identify the factors associated with psychotropic medication use. Patients ever using a psychotropic medication for anxiety grew from 57.4% in 2004 to 63.8% in 2009 (p<0.01). From 2004 to 2009, use of benzodiazepines (22.7-30.5%, p<0.01) and atypical antipsychotics (2.3-3.9%, p<0.01) increased. A high prevalence in the use of benzodiazepines (41.8% in 2004 to 48.8% in 2009) was observed among older adults. Older age, having insurance coverage, and poor health status were significantly associated with self-reported psychotropic medication use. An increase of psychotropic medication use from 2004 to 2009 was observed. A high prevalence and increasing trend in the use of benzodiazepines may warrant further attention given safety concerns in older adults.