Backward Compatible Identity-Based Encryption.

In this paper, we present a new identity-based encryption (IBE) system that is named Backward Compatible Identity-based Encryption (BC-IBE). Our BC-IBE is proposed to solve the problem caused by the out-of-synchronization between users' private keys and ciphertexts. Encryption systems such as revocable IBE or revocable Attribute-based Encryption (ABE) often require updating private keys to revoke users after a certain time period. However, in those schemes, an updated key can be used to decrypt the ciphertexts created only during the current time period. Once the key is updated and the previous keys are removed, the user, the owner of the updated key, will lose access to the past ciphertexts. In our paper, we propose BC-IBE that supports backward compatibility, to solve this problem. In our proposed system, user's private keys and ciphertexts can be updated periodically with time tags, and these processes can be used to revoke users who do not receive an updated key as the other revocable encryption does. However, in our proposed system, a private key newly issued to a user is backward compatible. This means that it decrypts not only the ciphertexts at the present time period but also all past ciphertexts. This implies that our proposed scheme guarantees the decryption of all encrypted data even if they are not synchronized. Compared to the existing revocable identity-based encryption system, our proposed BC-IBE has the advantage of simplifying key management and securely delegating ciphertext updates. Our proposed scheme only requires a single backward-compatible private key to decrypt all past ciphertexts created. Moreover, the ciphertext update process in our proposed scheme does not require any special privileges and does not require decryption. This means that this process can be securely delegated to a third-party server, such as a cloud server, and it prevents the potential leakage of secrets. For those reasons, BC-IBE is suitable for a system where users are more dynamic, such as the Internet-of-Things (IoT) network, or a system that regularly updates the data, like cloud data storage. In this paper, we provide the construction of BC-IBE and prove its formal security.

5G-AKA-FS: A 5G Authentication and Key Agreement Protocol for Forward Secrecy.

5G acts as a highway enabling innovative digital transformation and the Fourth Industrial Revolution in our lives. It is undeniable that the success of such a paradigm shift hinges on robust security measures. Foremost among these is primary authentication, the initial step in securing access to 5G network environments. For the 5G primary authentication, two protocols, namely 5G Authentication and Key Agreement (5G-AKA) and Improved Extensible Authentication Protocol Method for 3rd Generation Authentication and Key Agreement (EAP-AKA'), were proposed and standardized, where the former is for 3GPP devices, and the latter is for non-3GPP devices. Recent scrutiny has unveiled vulnerabilities in the 5G-AKA protocol, exposing it to security breaches, including linkability attacks. Moreover, mobile communication technologies are dramatically evolving while 3GPP has standardized Authentication and Key Management for Applications (AKMA) to reuse the credentials, generated during primary authentication, for 5G network applications. That makes it so significant for 5G-AKA to be improved to support forward secrecy as well as address security attacks. In response, several protocols have been proposed to mitigate these security challenges. In particular, they tried to strengthen security by reusing secret keys negotiated through the Elliptic Curve Integrated Encryption Scheme (ECIES) and countering linkability attacks. However, they still have encountered limitations in completing forward secrecy. Motivated by this, we propose an augmentation to 5G-AKA to achieve forward security and thwart linkability attacks (called 5G-AKA-FS). In 5G-AKA-FS, the home network (HN), instead of using its static ECIES key pair, generates a new ephemeral key pair to facilitate robust session key negotiation, truly realizing forward security. In order to thoroughly and precisely prove that 5G-AKA-FS is secure, formal security verification is performed by applying both BAN Logic and ProVerif. As a result, it is demonstrated that 5G-AKA-FS is valid. Besides, our performance comparison highlights that the communication and computation overheads are intrinsic to 5G-AKA-FS. This comprehensive analysis showcases how the protocol effectively balances between security and efficiency.

Effective gene delivery into human stem cells with a cell-targeting Peptide-modified bioreducible polymer.

Stem cells are poorly permissive to non-viral gene transfection reagents. In this study, we explored the possibility of improving gene delivery into human embryonic (hESC) and mesenchymal (hMSC) stem cells by synergizing the activity of a cell-binding ligand with a polymer that releases nucleic acids in a cytoplasm-responsive manner. A 29 amino acid long peptide, RVG, targeting the nicotinic acetylcholine receptor (nAchR) was identified to bind both hMSC and H9-derived hESC. Conjugating RVG to a redox-sensitive biodegradable dendrimer-type arginine-grafted polymer (PAM-ABP) enabled nanoparticle formation with plasmid DNA without altering the environment-sensitive DNA release property and favorable toxicity profile of the parent polymer. Importantly, RVG-PAM-ABP quantitatively enhanced transfection into both hMSC and hESC compared to commercial transfection reagents like Lipofectamine 2000 and Fugene. ∼60% and 50% of hMSC and hESC were respectively transfected, and at increased levels on a per cell basis, without affecting pluripotency marker expression. RVG-PAM-ABP is thus a novel bioreducible, biocompatible, non-toxic, synthetic gene delivery system for nAchR-expressing stem cells. Our data also demonstrates that a cell-binding ligand like RVG can cooperate with a gene delivery system like PAM-ABP to enable transfection of poorly-permissive cells.

Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-ß Accumulation in Alzheimer's Disease.

Amyloid-ß (Aß) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of ß-secretase or γ-secretase proves ineffective in reducing Aß accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aß generation without affecting crucial γ-secretase substrates. Dimerization of Lep9R3LC (diLep9R3LC) was confirmed by Ellman's test. The peptide-small interfering RNA (siRNA) complex ratio, particle size, and surface charge were analyzed using electrophoretic mobility shift assay, and dynamic light scattering, respectively. In a 3xTg mice model of Alzheimer's disease, diLep9R3LC:siRNA complexes were intravenously administered twice a week for 8 weeks. Assessments included gene silencing, protein expression, and behavioral improvement using reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, western blotting, Y-maze, and object recognition tests. The efficacy of Lep9R3LC dimerization was ~80% after a 3-d reaction by Ellman's test. In N2a cells, diLep9R3LC:siGSAP complexes achieved ~70% silencing at 48 h posttransfection. In 7-month-old male 3xTg mice, GSAP knockdown was ~30% in the cortex and ~50% in the hippocampus. The behavior improved in mice treated with diLep9R3LC:siGSAP complexes, showing a 60% increase in entries and an 80% increase object recognition. A novel dipeptide, diLep9R3LC, complexed with siRNA targeting GSAP (siGSAP), efficiently delivers siRNA to the mouse brain, targeting the hippocampus. The treatment inhibits Aß accumulation, reduces GSK-3ß-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LC:siGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases.

Controlling collagen gelation pH to enhance biochemical, structural, and biomechanical properties of tissue-engineered menisci.

Collagen-based hydrogels have been widely used in biomedical applications due to their biocompatibility. Enhancing mechanical properties of collagen gels remains challenging while maintaining biocompatibility. Here, we demonstrate that gelation pH has profound effects on cellular activity, collagen fibril structure, and mechanical properties of the fibrochondrocyte-seeded collagen gels in both short- and long-terms. Acidic and basic gelation pH, below pH 7.0 and above 8.5, resulted in dramatic cell death. Gelation pH ranging from 7.0 to 8.5 showed a relatively high cell viability. Furthermore, physiologic gelation (pH 7.5) showed the greatest collagen deposition while glycosaminoglycan deposition appeared independent of gelation pH. Scanning electron microscopy showed that neutral and physiologic gelation pH, 7.0 and 7.5, exhibited well-aligned collagen fibril structure on day 0 and enhanced collagen fibril structure with laterally joined fibrils on day 30. However, basic pH, 8.0 and 8.5, displayed a densely packed collagen fibril structure on day 0, which was also persistent on day 30. Initial equilibrium modulus increased with increasing gelation pH. Notably, after 30 days of culture, gelation pH of 7.5 and 8.0 showed the highest equilibrium modulus, reaching 150 -160 kPa. While controlling gelation pH is simply achieved compared with other strategies to improve mechanical properties, its influences on biochemical and biomechanical properties of the collagen gel are long-lasting. As such, gelation pH is a useful means to modulate both biochemical and biomechanical properties of the collagen-based hydrogels and can be utilized for diverse types of tissue engineering due to its simple application.

Removal of GAGs Regulates Mechanical Properties, Collagen Fiber Formation, and Alignment in Tissue Engineered Meniscus.

The complex fibrillar architecture of native meniscus is essential for proper function and difficult to recapitulate in vitro. In the native meniscus, proteoglycan content is low during the development of collagen fibers and progressively increases with aging. In vitro, fibrochondrocytes produce glycosaminoglycans (GAGs) early in culture, in contrast to native tissue, where they are deposited after collagen fibers have formed. This difference in the timing of GAG production hinders the formation of a mature fiber network in such in vitro models. In this study, we removed GAGs from collagen gel-based tissue engineered constructs using chondroitinase ABC (cABC) and evaluated the effect on the formation and alignment of collagen fibers and the subsequent effect on tensile and compressive mechanical properties. Removal of GAGs during maturation of in vitro constructs improved collagen fiber alignment in tissue engineered meniscus constructs. Additionally, removal of GAGs during maturation improved fiber alignment without compromising compressive strength, and this removal improved not only fiber alignment and formation but also tensile properties. The increased fiber organization in cABC-treated groups also appeared to influence the size, shape, and location of defects in these constructs, suggesting that treatment may prevent the propagation of large defects under loading. This data gives another method of modulating the ECM for improved collagen fiber formation and mechanical properties in tissue engineered constructs.

Mechanical performance of collagen gels is dependent on purity, α1/α2 ratio, and telopeptides.

This article describes the compositional, mechanical, and structural differences between collagen gels fabricated from different sources and processing methods. Despite extensive use of collagen in the manufacturing of biomaterials and implants, there is little information as to the variation in properties based on collagen source or processing methods. As such, differences in purity and composition may affect gel structure and mechanical performance. Using mass spectrometry, we assessed protein composition of collagen from seven different sources. The mechanics and gelation kinetics of each gel were assessed through oscillatory shear rheology. Scanning electron microscopy enabled visualization of distinct differences in fiber morphology. Mechanics and gelation kinetics differed with source and processing method and were found to correlate with differences in composition. Gels fabricated from telopeptide-containing collagens had higher storage modulus (144 vs. 54 Pa) and faster gelation (251 vs. 734 s) compared to atelocollagens, despite having lower purity (93.4 vs. 99.8%). For telopeptide-containing collagens, as collagen purity increased, storage modulus increased and fiber diameter decreased. As α1/α2 chain ratio increased, fiber diameter increased and gelation slowed. As such, this study provides an examination of the effects of collagen processing on key quality attributes for use of collagen gels in biomedical contexts.

Efficient engineering of human auricular cartilage through mesenchymal stem cell chaperoning.

A major challenge to the clinical translation of tissue-engineered ear scaffolds for ear reconstruction is the limited auricular chondrocyte (hAuC) yield available from patients. Starting with a relatively small number of chondrocytes in culture results in dedifferentiation and loss of phenotype with subsequent expansion. To significantly decrease the number of chondrocytes required for human elastic cartilage engineering, we co-cultured human mesenchymal stem cells (hMSCs) with HAuCs to promote healthy elastic cartilage formation. HAuCs along with human bone marrow-derived hMSCs were encapsulated into 1% Type I collagen at 25 million/mL total cell density with different ratios (HAuCs/hMSCs: 10/90, 25/75, 50/50) and then injected into customized 3D-printed polylactic acid (PLA) ridged external scaffolds, which simulate the shape of the auricular helical rim, and implanted subcutaneously in nude rats for 1, 3 and 6 months. The explanted constructs demonstrated near complete volume preservation and topography maintenance of the ridged "helical" feature after 6 months with all ratios. Cartilaginous appearing tissue formed within scaffolds by 3 months, verified by histologic analysis demonstrating mature elastic cartilage within the constructs with chondrocytes seen in lacunae within a Type II collagen and proteoglycan-enriched matrix, and surrounded by a neoperichondrial external layer. Compressive mechanical properties comparable to human elastic cartilage were achieved after 6 months. Co-implantation of hAuCs and hMSCs in collagen within an external scaffold efficiently produced shaped human elastic cartilage without volume loss even when hAuC comprised only 10% of the implanted cell population, marking a crucial step toward the clinical translation of auricular tissue engineering.

Detecting Audio Adversarial Examples in Automatic Speech Recognition Systems Using Decision Boundary Patterns.

Automatic Speech Recognition (ASR) systems are ubiquitous in various commercial applications. These systems typically rely on machine learning techniques for transcribing voice commands into text for further processing. Despite their success in many applications, audio Adversarial Examples (AEs) have emerged as a major security threat to ASR systems. This is because audio AEs are able to fool ASR models into producing incorrect results. While researchers have investigated methods for defending against audio AEs, the intrinsic properties of AEs and benign audio are not well studied. The work in this paper shows that the machine learning decision boundary patterns around audio AEs and benign audio are fundamentally different. Using dimensionality-reduction techniques, this work shows that these different patterns can be visually distinguished in two-dimensional (2D) space. This in turn allows for the detection of audio AEs using anomal- detection methods.

Combining TGF-ß1 and Mechanical Anchoring to Enhance Collagen Fiber Formation and Alignment in Tissue-Engineered Menisci.

Recapitulating the collagen fiber structure of native menisci is one of the major challenges in the development of tissue-engineered menisci. Native collagen fibers are developed by the complex interplay of biochemical and biomechanical signals. In this study, we optimized glucose and transforming growth factor-ß1 (TGF-ß1) concentrations in combination with mechanical anchoring to balance contributions of proteoglycan synthesis and contractile behavior in collagen fiber assembly. Glucose had a profound effect on the final dimensions of collagen-based constructs. TGF-ß1 influenced construct contraction rate and glycosaminoglycan (GAG) production with two half-maximal effective concentration (EC50) ranges, which are 0.23 to 0.28 and 0.53 to 1.71 ng/mL, respectively. At concentrations less than the EC50, for the GAG production and contraction rate, TGF-ß1 treatment resulted in less organized collagen fibers. At concentrations greater than the EC50, TGF-ß1 led to dense, disorganized collagen fibers. Between the two EC50 values, collagen fiber diameter and length increased. The effects of TGF-ß1 on fiber development were enhanced by mechanical anchoring, leading to peaks in fiber diameter, length, and alignment index. Fiber diameter and length increased from 7.9 ± 1.4 and 148.7 ± 16.4 to 17.5 ± 2.1 and 262.0 ± 13.0 µm, respectively. The alignment index reached 1.31, comparable to that of native tissue, 1.40. These enhancements in fiber architecture resulted in significant increases in tensile modulus and ultimate tensile stress (UTS) by 1.6- and 1.4-fold. Correlation analysis showed that tensile modulus and UTS strongly correlated with collagen fiber length, diameter, and alignment, while compressive modulus correlated with GAG content. These outcomes highlight the need for optimization of both biochemical and biomechanical cues in the culture environment for enhancing fiber development within tissue-engineered constructs.

Irreducible Lisfranc injury by tibialis anterior tendon entrapment: A case report.

RATIONALE: Lisfranc injuries are a dislocation of the metatarsal bones from the tarsal bone. Although closed reduction is possible in most cases of Lisfranc injury when attempted in the early stage, there are some rare cases for which open reduction is required. Herein we report a case of irreducible Lisfranc injury in a 34-year-old man who presented to our institution with painful swelling. PATIENT CONCERNS: We report a 34-year-old man presented to our institution with painful swelling after a fall from 1.0 m height. DIAGNOSES: We diagnosed it as irreducible Lisfranc injury by tibialis anterior tendon entrapment through plain radiologic study and surgical findings. INTERVENTIONS: Plain X-ray, C-arm fluoroscopy and open surgery were performed. OUTCOMES: We did a closed reduction under a C-arm fluoroscopic guide, but it was not successful. Thus, we had to do an open reduction of a Lisfranc dislocation. Upon exposure, we observed the entrapment of the tibialis anterior tendon between the medial and intermediate cuneiform bones. LESSONS: Our report is valuable in that it can contribute to the diagnosis and suggest a clue to the treatment of such a rare pathology. The knowledge in the rare case of entrapment of the tibialis tendon and the understanding of management will be useful when a irreducible Lisfranc dislocation is unsuccessful after an attempt at closed reduction.

Three-Dimensional-Printed External Scaffolds Mitigate Loss of Volume and Topography in Engineered Elastic Cartilage Constructs.

OBJECTIVE: A major obstacle in the clinical translation of engineered auricular scaffolds is the significant contraction and loss of topography that occur during maturation of the soft collagen-chondrocyte matrix into elastic cartilage. We hypothesized that 3-dimensional-printed, biocompatible scaffolds would "protect" maturing hydrogel constructs from contraction and loss of topography. DESIGN: External disc-shaped and "ridged" scaffolds were designed and 3D-printed using polylactic acid (PLA). Acellular type I collagen constructs were cultured in vitro for up to 3 months. Collagen constructs seeded with bovine auricular chondrocytes (BAuCs) were prepared in 3 groups and implanted subcutaneously in vivo for 3 months: preformed discs with ("Scaffolded/S") or without ("Naked/N") an external scaffold and discs that were formed within an external scaffold via injection molding ("Injection Molded/SInj"). RESULTS: The presence of an external scaffold or use of injection molding methodology did not affect the acellular construct volume or base area loss. In vivo, the presence of an external scaffold significantly improved preservation of volume and base area at 3 months compared to the naked group (P < 0.05). Construct contraction was mitigated even further in the injection molded group, and topography of the ridged constructs was maintained with greater fidelity (P < 0.05). Histology verified the development of mature auricular cartilage in the constructs within external scaffolds after 3 months. CONCLUSION: Custom-designed, 3D-printed, biocompatible external scaffolds significantly mitigate BAuC-seeded construct contraction and maintain complex topography. Further refinement and scaling of this approach in conjunction with construct fabrication utilizing injection molding may aid in the development of full-scale auricular scaffolds.

Nipple Engineering: Maintaining Nipple Geometry with Externally Scaffolded Processed Autologous Costal Cartilage.

INTRODUCTION: Nipple reconstruction is the essential last step of breast reconstruction after total mastectomy, resulting in improved general and aesthetic satisfaction. However, most techniques are limited by secondary scar contracture and loss of neo-nipple projection leading to patient dissatisfaction. Approximately, 16,000 patients undergo autologous flap breast reconstruction annually, during which the excised costal cartilage (CC) is discarded. We propose utilizing processed CC placed within biocompatible 3D-printed external scaffolds to generate tissue cylinders that mimic the shape, size and biomechanical properties of native human nipple tissue while mitigating contracture and projection loss. METHODS: External scaffolds were designed and then 3D-printed using polylactic acid (PLA). Patient-derived CC was processed by mincing or zesting, then packed into the scaffolds, implanted into nude rats and explanted after 3 months for volumetric, histologic and biomechanical analyses. Similar analyses were performed on native human nipple tissue and unprocessed CC. RESULTS: After 3 months in vivo, gross analysis demonstrated significantly greater preservation of contour, projection and volume of the scaffolded nipples. Mechanical analysis demonstrated that processing of the cartilage resulted in implant equilibrium modulus values closer to that of the human nipple. Histologic analysis showed the presence of healthy and viable cartilage after 3 months in vivo, invested with fibrovascular tissue. CONCLUSIONS: Autologous CC can be processed intraoperatively and placed within biocompatible external scaffolds to mimic the shape and biomechanical properties of the native human nipple. This allows for custom design and fabrication of individualized engineered autologous implants tailored to patient desire, without the loss of projection seen with traditional approaches.

Crystal-Induced Arthritis After Total Ankle Arthroplasty.

The causes of late-onset pain after total ankle replacement (TAR) are various, and include infection, subsidence, polyethylene spacer failure, osteolysis, and wear. There are few reports of late-onset pain caused by gouty attacks after total knee and hip arthroplasty. In addition, no research has reported gouty attacks after total ankle arthroplasty. Therefore, we report a case of a gouty attack after total ankle replacement. A 43-year-old man presented with pain after total ankle arthroplasty performed 5 years previously. We found a white-yellow crystalline deposit within the synovial tissue during ankle arthroscopy, confirmed by histologic examination.

Regulation of proteoglycan production by varying glucose concentrations controls fiber formation in tissue engineered menisci.

Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues and therefore commonly used as a biomaterial in tissue engineering applications. In the native environment, collagen fibers are arranged in a complex hierarchical structure that is often difficult to recreate in a tissue engineered construct. Small leucine rich proteoglycans as well as hyaluronan binding proteoglycans, aggrecan and versican, have been implicated in regulating fiber formation. In this study, we modified proteoglycan production in vitro by altering culture medium glucose concentrations (4500, 1000, 500, 250, and 125 mg/L), and evaluated its effect on the formation of collagen fibers inside tissue engineered meniscal constructs. Reduction of extracellular glucose resulted in a dose dependent decrease in total sulfated glycosaminoglycan (GAG) production, but minimal decreases of decorin and biglycan. However, fibromodulin doubled in production between 125 and 4500 mg/L glucose concentration. A peak in fiber formation was observed at 500 mg/L glucose concentration and corresponded with reductions in total GAG production. Fiber formation reduction at 125 and 250 mg/L glucose concentrations are likely due to changes in metabolic activity associated with a limited supply of glucose. These results point to proteoglycan production as a means to manipulate fiber architecture in tissue engineered constructs. STATEMENT OF SIGNIFICANCE: Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues; however achieving appropriate assembly and organization of collagen fibers in engineered connective tissues is a persistent challenge. Proteoglycans have been implicated in regulating collagen fiber organization both in vivo and in vitro, however little is known about methods to control proteoglycan production and the subsequent fiber organization in tissue engineered menisci. Here, we show that media glucose content can be optimized to control proteoglycan production and collagen fiber assembly, with optimal collagen fiber assembly occurring at sub-physiologic levels of glucose.

Extreme proximal migration of dislocated lunate over carpal ligament - A case report.

Dislocation of the lunate and proximal pole of the scaphoid with displacement of the fragments proximal to the radiocarpal joint, characterized as a total dislocation, is very rare, with only six cases reported. Dislocated lunate are generally located around the radiocarpal joint or within carpal ligament. However, there have been no reports of dislocated lunate over the carpal ligament. We present a patient with volar dislocation of the lunate that featured extreme migration to approximately 6 cm proximal to flexor digitorum superficialis through the transcarpal ligament.

An Anesthesia, Surgery, and Harvest Method for the Evaluation of Transpedicular Screws Using an In Vivo Porcine Lumbar Spine Model.

Pedicle screw fixation is the gold standard for the treatment of spinal diseases. However, many studies have reported the issue of loosening pedicle screws after spinal surgery, which is a serious concern. To address this problem, diverse types of pedicle screws have been examined to identify those with good fixation strength and osseointegration in spine bone. The porcine spine is a good alternative for the human spine in the evaluation of pedicle screws due to the anatomical size, mechanical characteristics, and cost. Although several studies have reported that pedicle screws are efficient in the porcine model, no study has described detailed protocols for the evaluation of a pedicle screw using the porcine model. Here, we describe a detailed method for evaluating transpedicular screws using an in vivo porcine lumbar spine model. The technical details for anesthesia, spine surgery, and harvest provided here will facilitate with the evaluation of the transpedicular screw fixation model.

Trileucine residues in a ligand-CPP-based siRNA delivery platform improve endosomal escape of siRNA.

siRNA entrapment within endosomes is a significant problem encountered with siRNA delivery platforms that co-opt receptor-mediated entry pathways. Attachment of a cell-penetrating peptide (CPP), such as nona-arginine (9R) to a cell receptor-binding ligand like the Rabies virus glycoprotein, RVG, allows effective siRNA delivery to the cytoplasm by non-endocytic pathways, but a significant amount of siRNA complexes also enters the cell by ligand-induced receptor endocytosis and remain localized in endosomes. Here, we report that the incorporation of trileucine (3 Leu) residues as an endo-osmolytic moiety in the peptide improves endosomal escape and intracellular delivery of siRNA. The trileucine motif did not affect early non-endosomal mechanism of cytoplasmic siRNA delivery but enhanced target gene silencing by >20% only beyond 24 h of transfection when siRNA delivery is mostly through the endocytic route and siRNA trapped in the endosomes at later stages were subject to release into cytoplasm. The mechanism may involve endosomal membrane disruption as trileucine residues lysed RBCs selectively under endosomal pH conditions. Interestingly <3 Leu or >3 Leu residues were not as effective, suggesting that 3 Leu residues are useful for enhancing cytoplasmic delivery of siRNA routed through endosomes.

Is retrograde drilling really useful for osteochondral lesion of talus with subchondral cyst?: A case report.

RATIONALE: Retrograde drilling is a well accepted procedure for osteochondral lesion of the talus and subchondral cyst with intact overlying cartilage. It has good results in most reports. Compared to anterograde drilling, retrograde drilling can protect the integrity of the articular cartilage. The purpose of this study was to evaluate the suitability of using retrograde drilling for osteochondral lesion with subchondral cyst and discuss the mechanism involved in the development of subchondral cyst. PATIENT CONCERNS: We report a 53-year-old man who had complained left ankle pain that lasted over 6 months which was exacerbated by walking. DIAGNOSES: We diagnosed it as osteochondral lesion of the talus with subchondral cyst. INTERVENTIONS: Plain X-ray, computed tomography, and magnetic resonance imaging (MRI) of the ankle. OUTCOMES: He undertook retrograde drilling without debridement of cartilage. After the surgery, the pain had been subsided for 1 year, although arthritic change had progressed. However, after 5 years of retrograde drilling, he revisited our hospital due to severe ankle pain. Plain X-ray and MRI showed arthritic change of the ankle and multiple cystic formation of talus. LESSONS: Retrograde drilling has some problem because this procedure is not theoretically correct when the development of a subchondral cyst in osteochondral lesion of the talus is considered. In addition, retrograde drilling may impair uninjured bone marrow of the talus, resulting in the development of multiple cystic formations.

Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice.

Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.