Lower Atrial Fibrillation Risk With Sodium-Glucose Cotransporter 2 Inhibitors Than With Dipeptidyl Peptidase-4 Inhibitors in Individuals With Type 2 Diabetes: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVES: Accumulating evidence shows that sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce adverse cardiovascular outcomes. However, whether SGLT2i, compared with other antidiabetic drugs, reduce the new development of atrial fibrillation (AF) is unclear. In this study, we compared SGLT2i with dipeptidyl peptidase-4 inhibitors (DPP-4is) in terms of reduction in the risk of AF in individuals with type 2 diabetes. METHODS: We included 42,786 propensity score-matched pairs of SGLT2i and DPP-4i users without previous AF diagnosis using the Korean National Health Insurance Service database between May 1, 2016, and December 31, 2018. RESULTS: During a median follow-up of 1.3 years, SGLT2i users had a lower incidence of AF than DPP-4i users (1.95 vs. 2.65 per 1,000 person-years; hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97; p=0.028]). In individuals without heart failure, SGLT2i users was associated with a decreased risk of AF incidence (HR, 0.70; 95% CI, 0.52-0.94; p=0.019) compared to DPP-4i users. However, individuals with heart failure, SGLT2i users was not significantly associated with a change in risk (HR, 1.04; 95% CI, 0.44-2.44; p=0.936). CONCLUSIONS: In this nationwide cohort study of individuals with type 2 diabetes, treatment with SGLT2i was associated with a lower risk of AF compared with treatment with DPP-4i.

Effect of hemoglobin A1c change on 24-month clinical outcomes in patients with diabetes after acute myocardial infarction.

BACKGROUND: The average glycated hemoglobin (HbA1c) may not accurately reflect glycemic control status during the mid-term after acute myocardial infarction (AMI). We aimed to evaluate changes in HbA1c and their effect on mid-term clinical outcomes in patients with diabetes and AMI. METHODS: We enrolled patients with diabetes (n = 967) who underwent HbA1c measurement in the Korean nationwide registry. These patients were categorized into three groups based on changes in HbA1c from index admission to the 1-year follow-up visit: a decrease in HbA1c > 1%, changes in HbA1c within 1%, and an increase in HbA1c > 1%. Clinical outcomes at 24 months were examined. RESULTS: The baseline HbA1c levels were 8.55 ±â€…0.85, 7.00 ±â€…0.98 and 7.07 ±â€…1.05 (P = 0.001) and HbA1c levels after 1 year were 6.62 ±â€…0.73, 7.05 ±â€…0.98 and 9.26 ±â€…1.59 (P = 0.001) for patients with 3 groups, respectively. Patients with a 1% decrease in HbA1c had significantly lower incidence of major adverse cardiovascular events (MACE), cardiac death, and rehospitalization after 24 months than those with a 1% increase in HbA1c. However, in the Cox regression analysis, a >1% decrease in HbA1c change was not an independent factor for MACE, cardiac death, and rehospitalization. CONCLUSIONS: Our analysis indicates that an HbA1c decrease of >1% within the first 12 months was not an independent prognostic factor until the 24-month mark. Therefore, standard diabetic control is recommended for patients with diabetes and AMI for up to 2 years.

Pharmacological Inhibition of LRRK2 Exhibits Neuroprotective Activity in Mouse Photothrombotic Stroke Model.

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson's disease (PD). Interestingly, recent studies have reported an increased risk of stroke in patients with PD harboring LRRK2 mutations, but there is no evidence showing the functional involvement of LRRK2 in stroke. Here, we found that LRRK2 kinase activity was significantly induced in the Rose-Bengal (RB) photothrombosis-induced stroke mouse model. Interestingly, stroke infarct volumes were significantly reduced, and neurological deficits were diminished by pharmacological inhibition of LRRK2 kinase activity using MLi-2, a brain-penetrant LRRK2 kinase inhibitor. Immunohistochemical analysis showed p-LRRK2 level in stroke lesions, co-localizing with mitophagy-related proteins (PINK, Parkin, LC3B, cytochrome c), suggesting their involvement in stroke progression. Overlapping p-LRRK2 with cytochrome c/TUNEL/JC-1 (an indicator of mitochondrial membrane potential) puncta in RB photothrombosis indicated LRRK2-induced mitochondrial apoptosis, which was blocked by MLi-2. These results suggest that pharmacological inhibition of LRRK2 kinase activity could attenuate mitochondrial apoptosis, ultimately leading to neuroprotective potential in stroke progression. In conclusion, LRRK2 kinase activity might be neuro-pathogenic due to impaired mitophagy in stroke progression, and pharmacological inhibition of LRRK2 kinase activity could be beneficial in reducing the risk of stroke in patients with LRRK2 mutations.

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-ß clearance in animal models of Alzheimer's disease.

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.

Peptide-mediated targeted delivery of SOX9 nanoparticles into astrocytes ameliorates ischemic brain injury.

Astrocytes are highly activated following brain injuries, and their activation influences neuronal survival. Additionally, SOX9 expression is known to increase in reactive astrocytes. However, the role of SOX9 in activated astrocytes following ischemic brain damage has not been clearly elucidated yet. Therefore, in the present study, we investigated the role of SOX9 in reactive astrocytes using a poly-lactic-co-glycolic acid (PLGA) nanoparticle plasmid delivery system in a photothrombotic stroke animal model. We designed PLGA nanoparticles to exclusively enhance SOX9 gene expression in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Our observations indicate that PLGA nanoparticles encapsulated with GFAP:SOX9:tdTOM reduce ischemia-induced neurological deficits and infarct volume through the prostaglandin D2 pathway. Thus, the astrocyte-targeting PLGA nanoparticle plasmid delivery system provides a potential opportunity for stroke treatment. Since the only effective treatment currently available is reinstating the blood supply, cell-specific gene therapy using PLGA nanoparticles will open a new therapeutic paradigm for brain injury patients in the future.

Gluteal Complex is important in External Snapping Hip: intraoperative identification of syndrome origin and endoscopic stepwise release-a case series.

PURPOSE: External snapping hip syndrome (ESHS) was historically attributed to isolated iliotibial band (ITB) contracture. However, the gluteus maximus complex (GMC) may also be involved. This study aimed to intraoperatively identify the ESHS origin and assess the outcomes of endoscopic treatment based on the identified aetiological type. METHODS: From 2008-2014, 30 consecutive patients (34 hips) with symptomatic ESHS cases refractory to conservative treatment underwent endoscopic stepwise "fan-like" release, gradually addressing all known reasons of ESHS: from the isolated ITB, through the fascial part of the GMC until a partial release of gluteus maximus femoral attachment occurred. Snapping was assessed intra-operatively after each surgical step and prospectively recorded. Functional outcomes were assessed via the MAHORN Hip Outcome Tool (MHOT-14). RESULTS: Twenty seven patients (31 hips) were available to follow-up at 24-56 months. In all cases, complete snapping resolution was achieved intra-operatively: in seven cases (22.6%) after isolated ITB release, in 22 cases (70.9%), after release of ITB + fascial part of the GMC, and in two cases (6.5%) after ITB + fascial GMC release + partial release of GM femoral insertion. At follow-up, there were no snapping recurrences and MHOT-14 score significantly increased from a pre-operative average of 46 to 93(p<0.001). CONCLUSION: Intraoperative identification and gradual addressing of all known causes of ESHS allows for maximum preservation of surrounding tissue during surgery while precisely targeting the directly involved structures. Endoscopic stepwise "fan-like" release of the ITB and GMC is an effective, tailor-made treatment option for ESHS regardless of the snapping origin in the patients with possibility to manually reproduce the snapping.

Employing the sustained-release properties of poly(lactic-co-glycolic acid) nanoparticles to reveal a novel mechanism of sodium-hydrogen exchanger 1 in neuropathic pain.

Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain.

Changes in alcohol consumption habits and risk of atrial fibrillation: a nationwide population-based study.

AIMS: Heavy alcohol consumption is an established risk factor for atrial fibrillation (AF). However, the association between habitual changes in heavy habitual drinkers and incident AF remains unclear. The aim of this study was to evaluate whether absolute abstinence or reduced drinking decreases incident AF in heavy habitual drinkers. METHODS AND RESULTS: Atrial fibrillation-free participants with heavy alcohol consumption registered in the Korean National Health Insurance Service database between 2005 and 2008 were enrolled. Habitual changes in alcohol consumption between 2009 and 2012 were classified as sustained heavy drinking, reduced drinking, and absolute abstinence. The primary outcome measure was new-onset AF during the follow-up. To minimize the effect of confounding variables on outcome events, inverse probability of treatment weighting (IPTW) analysis was performed. Overall, 19 425 participants were evaluated. The absolute abstinence group showed a 63% lower incidence of AF (IPTW hazard ratio: 0.379, 95% confidence interval: 0.169-0.853) than did the sustained heavy drinking group. Subgroup analysis identified that abstinence significantly reduced incident AF in participants with normal body mass index and without hypertension, diabetes, dyslipidaemia, heart failure, stroke, chronic kidney disease, or coronary artery disease (all P-value <0.05). There was no statistical difference in incident AF in participants with reduced drinking compared with sustained heavy alcohol group. CONCLUSION: Absolute abstinence could reduce the incidence of AF in heavy alcohol drinkers. Comprehensive clinical measures and public health policies are warranted to motivate alcohol abstinence in heavy drinkers.

In this study of 19 425 participants, we investigated whether alcohol consumption reduction was associated with lower risk of incident atrial fibrillation (AF) in individuals with chronic heavy alcohol consumption. The absolute abstinence significantly reduced incident AF, but reducing alcohol consumption was not associated with a lower incident AF. The benefit of absolute abstinence for incidence of AF was significantly identified in participants with normal body mass index and without hypertension, diabetes, dyslipidaemia, heart failure, stroke, chronic kidney disease, or coronary artery disease.

Effects of Midcheek Lift According to Dissection Plane and Range: An Anatomical Study.

BACKGROUND: Midcheek lift has been performed for cosmetic or reconstructive surgery of the lower eyelid. For midcheek lift through the subciliary incision, preperiosteal and subperiosteal dissections are the most often implemented, with good clinical outcomes. However, a comparative assessment of the effects of these 2 methods had not been conducted. OBJECTIVES: In this study we compared the effects of midcheek lift according to preperiosteal or subperiosteal plane and range of midfacial dissection. METHODS: Forty hemifaces of 20 fresh cadavers were dissected. One side of the hemiface underwent preperiosteal dissection, and the other side underwent subperiosteal dissection. After dissections of 5, 10, 15, 20, and 30 mm and all of the midcheek area from the inferior orbital rim, the length of the elevated lid-cheek junction was measured by placing upward traction on the lateral portion of the lower lid. RESULTS: In both methods, the length of the midcheek lift increased as the dissection progressed, and the length of the lift on the lateral side was greater than that on the medial side. The length of the pulled skin in the preperiosteal group was the greatest in most cases. However, in the full dissection cases, the midcheek lift length was not statistically different between the 2 surgical methods, especially on the lateral side. CONCLUSIONS: Flap elevation in lower blepharoplasty surgery can be predicted based on the surgical method and dissection range. Implementing a surgical plan that takes this into account can enhance both reconstruction and aesthetic surgery outcomes in the midcheek area.

Knee extension contracture with fixed anterior tibia subluxation treated with PCL release and quadricepsplasty: a case report.

58-year-old male presented with knee extension contracture (25°) with iatrogenic fixed anterior tibial subluxation. Consecutive arthroscopic arthrolysis, manipulation under anesthesia, and quadriceps-Z-plasty during one surgery failed to restore flexion. Therefore, shortened posterior cruciate ligament was released, which eliminated subluxation and allowed 115° flexion. Despite physiotherapy, flexion progressively decreased to 70° postoperatively. Revision quadricepsplasty by transverse incisions restored 120° of flexion maintained at 31-months follow-up. International Knee Documentation Committee increased 4/87- > 50/87, Knee injury and Osteoarthritis Outcome 7/100- > 68/100 at follow-up. Posterior cruciate ligament release and repeated quadricepsplasty could be a viable salvage option in severe extension contracture with fixed anterior tibial subluxation.

Cardiac osteosarcoma: a case report and literature review.

Background: Primary cardiac tumors are rare, and malignant primary cardiac tumors are even rarer. Cardiac osteosarcoma is a very rare type of malignant primary cardiac tumor with limited reported cases. We present a case report of cardiac osteosarcoma and review its characteristics and the related literature. Case summary: A 44-year-old female patient without a specific medical history presented with intermittent dyspnea that started 1 month prior to presentation. A heterogeneous mass was observed in the left atrium on echocardiography and a large mass was observed in the left atrium on computed tomography. Surgery was performed under the suspicion of atypical cardiac myxoma, and the tumor was successfully removed. However, postoperative histopathological examination revealed cardiac osteosarcoma. The patient underwent chemotherapy and has been well maintained without recurrence for 10 years. Conclusion: We present a case report of the echocardiographic features and treatment strategies for cardiac osteosarcoma, an extremely rare cardiac tumor. Multimodal imaging can be helpful; however, a histological diagnosis through surgical resection is essential. Appropriate treatment and follow-up based on histological findings are necessary.

Incomplete meniscal healing in early second-look arthroscopy does not indicate failure of repair: a case series.

PURPOSE: To assess if incomplete meniscal healing during second-look arthroscopy at six to eight weeks after all-inside suture hook meniscus repair results in longer-term failure of repair in patients with restored knee stability. METHODS: From 2008 to 2013, 41 patients with post-traumatic, longitudinal, vertical, complete meniscal tears with concomitant ACL injury were treated via a two-stage surgical procedure and prospectively evaluated. In the first stage, all-inside meniscus repair was performed using suture hook passers and non-absorbable sutures. In total, there were 26 medial and 16 lateral meniscus tears. A second-stage ACL reconstruction, performed six to eight weeks later, served as an early second-look arthroscopic evaluation of meniscal healing. Clinical follow-up was performed at a minimum of 24 months. RESULTS: Second-look arthroscopy revealed 31 cases (75.6%) of complete and ten cases (24.4%) of incomplete meniscal healing. Two patients were lost prior to follow-up, and three were excluded due to recurrent instability. Therefore, 36 patients were assessed at the final follow-up. All patients with complete meniscal healing during second-look arthroscopy achieved clinical success at follow-up. Six out of nine (66.7%) of patients with incomplete meniscal healing during second-look arthroscopy achieved clinical success at follow-up (p = 0.012). One saphenous neuropathy occurred (2.4%). CONCLUSION: Incomplete meniscal healing during early second-look arthroscopy after all-inside meniscal repair using suture hook passers and non-absorbable sutures did not necessarily result in longer-term failure in patients with restored knee stability. The described method of meniscal repair was associated with a low rate of symptomatic re-tears and complications.

CRIF1 siRNA-Encapsulated PLGA Nanoparticles Suppress Tumor Growth in MCF-7 Human Breast Cancer Cells.

Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.

A multi-targeting bionanomatrix coating to reduce capsular contracture development on silicone implants.

BACKGROUND: Capsular contracture is a critical complication of silicone implantation caused by fibrotic tissue formation from excessive foreign body responses. Various approaches have been applied, but targeting the mechanisms of capsule formation has not been completely solved. Myofibroblast differentiation through the transforming growth factor beta (TGF-ß)/p-SMADs signaling is one of the key factors for capsular contracture development. In addition, biofilm formation on implants may result chronic inflammation promoting capsular fibrosis formation with subsequent contraction. To date, there have been no approaches targeting multi-facted mechanisms of capsular contracture development. METHODS: In this study, we developed a multi-targeting nitric oxide (NO) releasing bionanomatrix coating to reduce capsular contracture formation by targeting myofibroblast differentiation, inflammatory responses, and infections. First, we characterized the bionanomatrix coating on silicon implants by conducting rheology test, scanning electron microcsopy analysis, nanoindentation analysis, and NO release kinetics evaluation. In addition, differentiated monocyte adhesion and S. epidermidis biofilm formation on bionanomatrix coated silicone implants were evaluated in vitro. Bionanomatrix coated silicone and uncoated silicone groups were subcutaneously implanted into a mouse model for evaluation of capsular contracture development for a month. Fibrosis formation, capsule thickness, TGF-ß/SMAD 2/3 signaling cascade, NO production, and inflammatory cytokine production were evaluated using histology, immunofluorescent imaging analysis, and gene and protein expression assays. RESULTS: The bionanomatrix coating maintained a uniform and smooth surface on the silicone even after mechanical stress conditions. In addition, the bionanomatrix coating showed sustained NO release for at least one month and reduction of differentiated monocyte adhesion and S. epidermidis biofilm formation on the silicone implants in vitro. In in vivo implantation studies, the bionanomatrix coated groups demonstrated significant reduction of capsule thickness surrounding the implants. This result was due to a decrease of myofibroblast differentiation and fibrous extracellular matrix production through inhibition of the TGF-ß/p-SMADs signaling. Also, the bionanomatrix coated groups reduced gene expression of M1 macrophage markers and promoted M2 macrophage markers which indicated the bionanomatrix could reduce inflammation but promote healing process. CONCLUSIONS: In conclusion, the bionanomatrix coating significantly reduced capsular contracture formation and promoted healing process on silicone implants by reducing myfibroblast differentiation, fibrotic tissue formation, and inflammation. A multi-targeting nitric oxide releasing bionanomatrix coating for silicone implant can reduce capsular contracture and improve healing process. The bionanomatrix coating reduces capsule thickness, α-smooth muscle actin and collagen synthesis, and myofibroblast differentiation through inhibition of TGF-ß/SMADs signaling cascades in the subcutaneous mouse models for a month.

MiR-146a encapsulated liposomes reduce vascular inflammatory responses through decrease of ICAM-1 expression, macrophage activation, and foam cell formation.

Vascular insults can create an inflammatory cascade involving endothelial cell, smooth muscle cell, and macrophage activation which can eventually lead to vascular disease such as atherosclerosis. Several studies have identified microRNA 146a's (miR-146a) anti-inflammatory potential based on its role in regulating the nuclear factor kappa beta (NF-κß) pathway. Therefore, in this study, we introduced exogenous miR-146a encapsulated by liposomes to lipopolysaccharide (LPS) stimulated vascular cells and macrophages to reduce inflammatory responses. First, the miR-146a encapsulated liposomes showed uniform size (radius 96.4 ± 4.22 nm) and round shape, long term stability (at least two months), high encapsulation efficiency (69.73 ± 0.07%), and were well transfected to human aortic endothelial cells (HAECs), human aortic smooth muscle cells (SMCs), and human differentiated monocytes (U937 cells). In addition, we demonstrated that miR-146a encapsulated liposomes reduced vascular inflammation responses in HAECs and SMCs through inhibition of ICAM-1 expression and decreased monocyte adhesion. In macrophages, miR-146a liposome treatment demonstrated decreased production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), as well as reduced oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation. Thus, based on these results, miR-146a encapsulated liposomes may be promising for reducing vascular inflammation by targeting its multiple associated mediators.

PINK1 siRNA-loaded poly(lactic-co-glycolic acid) nanoparticles provide neuroprotection in a mouse model of photothrombosis-induced ischemic stroke.

PTEN-induced kinase 1 (PINK1) is a well-known critical marker in the pathway for mitophagy regulation as well as mitochondrial dysfunction. Evidence suggests that mitochondrial dynamics and mitophagy flux play an important role in the development of brain damage from stroke pathogenesis. In this study, we propose a treatment strategy using nanoparticles that can control PINK1. We used a murine photothrombotic ischemic stroke (PTS) model in which clogging of blood vessels is induced with Rose Bengal (RB) to cause brain damage. We targeted PINK1 with poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles loaded with PINK1 siRNA (PINK1 NPs). After characterizing siRNA loading in the nanoparticles, we assessed the efficacy of PINK1 NPs in mice with PTS using immunohistochemistry, 1% 2,3,5-triphenyltetrazolium chloride staining, measurement of motor dysfunction, and Western blot. PINK1 was highly expressed in microglia 24 h after PTS induction. PINK1 siRNA treatment increased phagocytic activity, migration, and expression of an anti-inflammatory state in microglia. In addition, the PLGA nanoparticles were selectively taken up by microglia and specifically regulated PINK1 expression in those cells. Treatment with PINK1 NPs prior to stroke induction reduced expression of mitophagy-inducing factors, infarct volume, and motor dysfunction in mice with photothrombotic ischemia. Experiments with PINK1-knockout mice and microglia depletion with PLX3397 confirmed a decrease in stroke-induced infarct volume and behavioral dysfunction. Application of nanoparticles for PINK1 inhibition attenuates RB-induced photothrombotic ischemic injury by inhibiting microglia responses, suggesting that a nanomedical approach targeting the PINK1 pathway may provide a therapeutic avenue for stroke treatment.

Anatomy of the greater palatine foramen and canal and their clinical significance in relation to the greater palatine artery: a systematic review and meta-analysis.

PURPOSE: Accurate knowledge of greater palatine foramen (GPF) and greater palatine canal (GPC) anatomy is necessary to avoid injury to the greater palatine artery (GPA) when performing a variety of anesthesiologic, dental or surgical procedures. The aim of this paper was to perform a systematic review and meta-analysis of literature on the anatomy and localization of bony structures associated with the GPA, namely the GPF and GPC. METHODS: A systematic literature search was performed using PubMed, Embase, ScienceDirect, and Web of Science databases. Seventy-five studies were included in the meta-analysis (n = 22,202 subjects). RESULTS: The meta-analysis showed that the GPF is positioned 17.21 mm (95% CI = 16.34-18.09 mm) from the posterior nasal spine, 2.56 mm (95% CI = 1.90-3.22 mm) from the posterior border of the hard palate, 46.24 mm (95% CI = 44.30-48.18 mm) from the anterior nasal spine, 15.22 mm (95% CI = 15.00-15.43 mm) from the midline maxillary suture, 37.32 mm (95% CI = 36.19-38.45 mm) from the incisive foramen, and opposite the third maxillary molar (M3) in 64.9% (58.7-70.7%) of the total population. CONCLUSION: An up-to-date, comprehensive analysis of GPF and GPC clinical anatomy is presented. The results from this evidence-based anatomical study provides a unified set of data to aid clinicians in their practice.

Autophagy Dysfunction in a Diabetic Peripheral Neuropathy Model.

BACKGROUND: The relationship between autophagy and diabetic peripheral neuropathy (DPN) has been highlighted in few reports. Using an animal model, the authors investigated the relationship between autophagy and DPN, focused particularly on changes in autophagy in Schwann cells. METHODS: The ultrastructural features of DPN mice were evaluated in vivo using transmission electron microscopy. Dysfunction of autophagy in DPN was evaluated using immunofluorescence microscopy and Western blot analysis of proteins related to autophagy, including Beclin1, LC3, and p62. Reactive oxygen species levels were measured in vitro in glucose-treated Schwann cells. Dysfunction of autophagy in glucose-treated Schwann cells was examined by immunofluorescence microscopy and Western blot analysis. RESULTS: Reduced myelin thickness and axonal shrinkage were observed in the sciatic nerves of DPN mice. Reactive oxygen species levels were increased in Schwann cells treated with high glucose ( P < 0.05). The expression of Beclin1 was increased in DPN mice and Schwann cells treated with high glucose ( P < 0.05), whereas the expression of LC3-II/LC3-I ratio and p62 were decreased in DPN mice and Schwann cells treated with high glucose ( P < 0.05). CONCLUSIONS: These results suggest that increased levels of reactive oxygen species induced by high glucose may contribute to autophagy dysfunction in Schwann cells. Autophagy dysfunction especially in Schwann cells may be an underlying cause of DPN. CLINICAL RELEVANCE STATEMENT: This study presents the pathological mechanism of diabetic peripheral neuropathy.

Influence of respiratory movement during post mastectomy radiotherapy on targets and heart for breast cancer.

BACKGROUND/AIM: This study aimed to compare the dosimetric consequences of respiratory movement in volumetric-modulated arc therapy (VMAT) and three-dimensional conformal radiation therapy (3D-CRT) during postmastectomy radiation therapy, including internal mammary nodes (IMNs). MATERIALS AND METHODS: Respiratory motion was implemented to a phantom using a dynamic device. The plans were delivered during cranial-caudal and ventral-dorsal movement in 5-mm (R05) and 10-mm (R10) amplitudes. RESULTS: At the IMN, the dose errors were -2.8% (R05) and -6.2% (R10) for 3D-CRT and -4.9% (R05) and -8.5% (R10) for VMAT. The dose errors in chest wall were -.5% (R05) and -6.0% (R10) for 3D-CRT and -1.9% (R05) and -5.3% (R10) for VMAT. The left anterior descending doses showed significantly small absolute values. The gamma pass rates of VMAT were higher than those of 3D-CRT. CONCLUSIONS: The benefit of VMAT technique in dose distribution was maintained, except in occasional instances of large breathing motion.

Arthroscopic Trans-septal Portal of the Knee With Direct Visualization and No Need for Posterolateral Portal Creation.

Arthroscopic visualization and access of the posterior knee are limited when using standard anterior and posterior portals. The creation of a trans-septal portal allows for complete access to the posterior compartment as arthroscopic instruments are able to be passed back and forth between the posteromedial and posterolateral compartments. Due to the close proximity of the popliteal artery and its branches, precise portal placement and safe orientation of arthroscopic instruments are critical to avoid iatrogenic injury. The conventional technique of trans-septal portal creation, involving a posterolateral portal, can be difficult in some cases. To overcome these obstacles, a posteromedial technique of trans-septal portal creation is presented. By using the medial parapatellar portal as the viewing portal, our technique allows for direct visualization of the posterior septum on each step of creation of the trans-septal portal, eliminating the need for "blind" maneuvers. What is more, no posterolateral portal is needed, decreasing the risk of potential complications. Using the posterior cruciate ligament fibers as a main landmark for trans-septal portal placement, preservation of the posterior part of the septum is achieved. This ensures optimal safe-margin distance away from the popliteal neurovascular bundle and making the technique safe and reproducible.