Peripheral intravascular lithotripsy to facilitate transfemoral transcatheter aortic valve replacement - Defining optimal treatable peripheral arterial disease burden.

BACKGROUND: Transfemoral transcatheter aortic valve replacement (TF-TAVR) has proven superior to alternative access. However, some patients evaluated for TF-TAVR are unfit secondary to peripheral arterial disease (PAD). Peripheral intravascular lithotripsy (IVL) can facilitate femoral access. This study aimed to characterize optimal lesions that can be treated with IVL. METHODS: Single-center, retrospective analysis of an institutional database, queried from 1/2018 through 7/2023 for all patients who underwent TAVR. Patients who received IVL-facilitated transfemoral access were analyzed. RESULTS: Of 2862 TAVR cases identified, 92 (3.2 %) underwent lithotripsy. The IVL-facilitated cohort had a mean age of 78 ± 9.2 years and 45 % were female. The right common iliac artery was most treated (47). Most IVL was performed with 7-mm balloons (73.9 %). All cases were successful. 30-day mortality was 1.1 % (1/92). CONCLUSIONS: In our cohort, complications after IVL-facilitated TF-TAVR were more common with small vessel diameter (≤4.7 mm), significant luminal loss (>50 % stenosis), and heavy calcium burden (arc calcification >180°). The findings support the use of IVL to expand the population of patients who can undergo TF-TAVR without the increased risks associated with the various forms of alternative access. SUMMARY FOR ANNOTATED TABLE OF CONTENTS: IVL-facilitated TF-TAVR is safe and feasible. Despite its introduction to TAVR clinical practice in 2018, IVL-facilitated TF-TAVR is not regularly performed and could increase the population of patients eligible for TF-TAVR.

Multilocular Radiolucent Pathology in the Body and Ramus of the Mandible: A Case Report.

Odontogenic keratocyst (OKC), a type of epithelial developmental cyst, is frequently found in the jaw region. It has invasive characteristics such as satellite cysts, rapid progression, and tissue expansion. The OKC often favors the mandibular angle and ascending ramus. OKC symptoms include pain, swelling, displacement or malpositioning of adjacent teeth, and erosion or thinning of the limited or no bucco-lingual cortical expansion. There is radiographic evidence of a distinct, often scalloped, radiolucent lesion with a characteristic "soap bubble" or "honeycomb" appearance. This article reports a female patient, aged 40 years, with the main concern of unilateral pain and swelling of the mandibular left side and the provisional diagnosis of ameloblastoma. After histopathological examination, the final diagnosis of the patient was OKC. This article also includes previously published literature on OKC with differential diagnosis and relevant clinical and radiologic findings of the case.

Ultrasound enhancing agents in cardiovascular imaging: expanding horizons beyond coronary arteries.

From its inception as a two-dimensional snapshot of the beating heart, echocardiography has become an indelible part of cardiovascular diagnostics. The integration of ultrasound enhancing agents (UEAs) marks a pivotal transition, enhancing its diagnostic acumen beyond myocardial perfusion. These agents have refined echocardiography's capacity to visualize complex cardiac anatomy and pathology with unprecedented clarity, especially in non-coronary artery disease contexts. UEAs aid in detailed assessments of myocardial viability, endocardial border delineation in left ventricular opacification, and identification of intracardiac masses. Recent innovations in UEAs, accompanied by advancements in echocardiographic technology, offer clinicians a more nuanced view of cardiac function and blood flow dynamics. This review explores recent developments in these applications and future contemplated studies.

Hoffa's fat pad ganglion cyst of the knee: a case report of a rare cause of knee pain and swelling.

Introduction and importance: Hoffa's fat pad (HFP), also known as infrapatellar fat pad, is one of the three fat pads in the knee. Ganglion cyst (GC) rarely arises from HFP which presents knee pain and swelling. Case presentation: A 43-year-old female presented with left knee pain for 1 year and swelling in her left knee for 6 months. Clinical examination revealed a palpable swelling of size around 3 cm×2 cm over the anteromedial aspect of the left knee. The size of the swelling increased on extension and decreased on flexion of the knee. A musculoskeletal ultrasound of the left knee revealed a lobulated anechoic lesion of size ∼2.3 cm×2 cm in HFP. Open excision of cystic mass through medial parapatellar approach was done, and histopathological examination showed findings consistent with GC. At 6 months follow-up, there was no residual swelling and no recurrence. She was symptom-free on her recent evaluation after 1 year of operation. Clinical discussion: GCs arising from HFP are much rarer among the cysts around the knee. Diagnosis is primarily done by magnetic resonance imaging. However, the use of ultrasonography has grown in the diagnosis of the GC. Among different modalities of treatment, open excision is the most recommended to prevent recurrence and incomplete resection. Conclusions: This case illustrates the importance of ultrasonography in the early diagnosis of HFP GC and reserving more costly and time-consuming imaging modality magnetic resonance imaging for localizing the extent of the cyst. We recommend an open resection to avoid recurrence and incomplete resection of the cyst.

Quantitative determination of C-polysaccharide in Streptococcus pneumoniae capsular polysaccharides by enzyme-linked immunosorbent assay.

Capsular polysaccharides of Streptococcus pneumoniae are used in pneumococcal polysaccharide and protein-conjugate vaccines. Cell-wall polysaccharide (C-Ps) is a critical impurity that must be kept at low levels in purified polysaccharide preparations. Hence, accurate and precise methods for determining C-Ps are needed. Currently available methods include nuclear magnetic resonance (NMR) spectroscopy and high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Both these methods suffer from their own limitations; therefore, we developed a simple and efficient enzyme-linked immunosorbent assay (ELISA) for accurate and precise quantification of C-Ps in samples of any serotype of pneumococcal capsular polysaccharide without interference. We quantified C-Ps in preparations of 14 serotype polysaccharides using newly developed ELISA method and compared the results with C-Ps values obtained using two previously reported methods, 1H NMR and HPAEC-PAD. The C-Ps value determined using 1H NMR for serotype 5 was 21.08%, whereas the values obtained using HPAEC-PAD and ELISA were 2.38% and 2.89% respectively, indicating some interference in 1H NMR method. The sensitivity of the ELISA method is higher because the sample is used directly unlike HPAEC-PAD method where sample is subjected to harsh treatment, such as acid digestion and quantify C-Ps based on peak area of ribitol or AAT. Furthermore, 1H NMR and HPAEC-PAD are expensive and laborious methods. Our work, underscores the simple and efficient ELISA that can be used for quantification of C-Ps in pneumococcal polysaccharide preparations.

Multiwavelength Photoacoustic Doppler Flowmetry of Living Microalgae Cells.

Photoacoustics can provide a direct measurement of light absorption by microalgae depending on the photosynthesis pigment within them. In this study, we have performed photoacoustic flowmetry on living microalgae cells to measure their flow characteristics, which include flow speed, flow angle, flow direction, and, more importantly, the photoacoustic absorption spectrum, all by observing the photoacoustic Doppler power spectra during their flowing state. A supercontinuum pulsed laser with a high repetition frequency is used as the light source: through intensity modulation at a specified frequency, it can provide wavelength-selectable excitation of a photoacoustic signal centered around this frequency. Our approach can be useful to simultaneously measure the flow characteristics of microalgae and easily discriminate their different species with high accuracy in both static and dynamic states, thus facilitating the study of their cultivation and their role in our ecosystem.

Targeting Peptidylarginine Deiminase 3 to Efficiently Suppress Herpes Simplex Virus Type 2 Infection.

Protein expression is regulated through multiple mechanisms, including post-translational modifications (PTMs), which can alter protein structure, stability, localization, and function. Among these, citrullination stands out due to its ability to convert arginine residues into citrulline, altering protein charge and mass. This modification is catalyzed by calcium-dependent protein arginine deiminases (PADs), enzymes implicated in various inflammatory diseases. We have recently shown that human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) exploit these enzymes to enhance their replication capabilities. Although the role of PADs in HCMV and HSV-1 infections is well documented, their involvement in HSV-2 infection has not yet been thoroughly investigated. Here, we demonstrate that HSV-2 manipulates the overall protein citrullination profile by activating three PAD isoforms: PAD2, PAD3, and PAD4. However, as previously observed during HSV-1 infection, PAD3 is the most significantly upregulated isoform, both at the mRNA and protein levels. Consistently, we demonstrate that inhibiting PAD3, either through the specific inhibitor CAY10727 or via CRISPR/Cas9-mediated gene silencing, markedly reduces HSV-2 replication and viral protein expression. Lastly, we show that CAY10727 displays an IC50 value of 0.3 µM, which is extremely close to what was previously observed for HSV-1. Overall, our findings highlight the crucial role of PAD3 in the life cycle of HSV-2 and suggest that the targeted inhibition of PAD3 may represent a promising approach for treating HSV-2 infections, especially in cases resistant to existing antiviral therapies.

Benefits and Challenges of Drug-Coated Balloons in Peripheral Artery Disease: From Molecular Mechanisms to Clinical Practice.

Multiple clinical trials have reported favorable outcomes after drug-coated balloon therapy for peripheral artery disease in above-the-knee and below-the-knee lesions and in both de novo and in-stent restenosis. However, there are still insufficient data to identify and tackle the risk factors associated with a higher risk of restenosis, which is the primary concern for patients who are treated with an endovascular approach. A modern armamentarium, which includes improved lesion preparation techniques such as plaque modification balloons, mechanical atherectomy, intravascular lithotripsy, and imaging, is crucial for obtaining better long-term clinical outcomes. Moreover, a better understanding of the molecular properties of drug-coated balloons has led to improved devices that could tackle the shortcomings of previous generations. This comprehensive review focuses on drug-coated balloon technology as a tool to treat peripheral artery disease and the effects of the molecular mechanisms involved in preventing vascular restenosis.

Novel mutation in the IGHMBP2 gene in spinal muscular atrophy with respiratory distress type 1: A case report.

Background: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive hereditary disease. Immunoglobulin µ-binding protein 2 (IGHMBP2) gene mutations are the main cause of SMARD1. Case presentation: Here we describe a female infant with SMARD1 carrying heterozygous mutations in IGHMBP2 genes, c.1334A > C(p.His445Pro) and c.1666C > G(p.His556Asp), which were inherited from both parents. Clinical presentations included frequent respiratory infections, respiratory failure, distal limb muscle weakness, and fat pad found at the distal toe. Conclusions: c.1666C > G(p.His556Asp) is a novel site mutation in IGHMBP2. This case expanded knowledge on the genetic profile of SMARD1 and it provides a basis for genetic testing of parents and for genetic counseling to assess the risk of fetal disease.

The emerging role of neutrophil extracellular traps in ulcerative colitis.

Ulcerative colitis (UC) is characterized by chronic non-recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. Currently, new targeted therapies are urgently needed for UC, and neutrophil extracellular traps (NETs) are new therapeutic options. NETs are DNA-based networks released from neutrophils into the extracellular space after stimulation, in which a variety of granule proteins, proteolytic enzymes, antibacterial peptides, histones, and other network structures are embedded. With the deepening of the studies on NETs, their regulatory role in the development of autoimmune and autoinflammatory diseases has received extensive attention in recent years. Increasing evidence indicates that excess NETs exacerbate the inflammatory response in UC, disrupting the structure and function of the intestinal mucosal barrier and increasing the risk of thrombosis. Although NETs are usually assigned a deleterious role in promoting the pathological process of UC, they also appear to have a protective role in some models. Despite such progress, comprehensive reviews describing the therapeutic promise of NETs in UC remain limited. In this review, we discuss the latest evidence for the formation and degradation of NETs, focusing on their double-edged role in UC. Finally, the potential implications of NETs as therapeutic targets for UC will be discussed. This review aims to provide novel insights into the pathogenesis and therapeutic options for UC.

Evolving Trends in the Management of Diabetic Foot Ulcers: A Narrative Review.

The prevalence of diabetic foot ulcers (DFUs) is projected to increase worldwide, which necessitates a review of the current management principles and the development of new approaches to care. The principles of management involve proper glycemic control, infection control, pressure redistribution, wound care debridement, and revascularization. Other modalities of management, such as hyperbaric oxygen therapy and negative wound pressure therapy, are also being explored. While some aspects of DFU care lack high-quality evidence, a multidisciplinary approach incorporating these evolving trends has the potential to improve outcomes and prevent lower extremity amputations in this challenging condition. This review highlights the need for further research to establish definitive treatment protocols for optimal DFU management.

Evaluation of the therapeutic potential of infrapatellar fat pad adipose-derived stem cells and their secretome for regenerating knee articular cartilage in a rat model of osteoarthritis.

Background: Mesenchymal stem cell (MSC) therapy has ameliorative effects for treating knee osteoarthritis (KOA) disease. Moreover, there is a growing interest in using MSCs-derived secretome (Sec) containing trophic factors secreted by MSCs for KOA treatment. Recently, some studies have suggested that the combination of MSCs and Sec has the potential to treat the diseases. Aims: This study aimed to evaluate the ameliorative effects of combined administration of infrapatellar fat pad (IPFP)-derived MSCs, a type of adipose-derived stem cells (ASCs), for treating degenerated cartilage in a rat model of KOA. Methods: IPFP-ASCs were isolated from the IPFP of male rats. Sec was obtained from IPFP-ASCs in the fourth passage. Eight weeks after the induction of KOA by collagenase II, the rats were divided into 5 groups (n=5), including a control group with no treatment, and four experimental groups that received sodium hyaluronate (Hyalgan®, Hya), ASCs, Sec, and IPFP-ASCs+Sec, respectively by an infrapatellar injection. To perform the pathological and radiological evaluations, the animals were sacrificed 8 weeks later. Results: Our findings indicated that combined administration of the IPFP-ASCs and Sec statistically (P<0.05) improved scores of medial tibial and femoral condyles and medial fabella osteophytes. Also, it statistically (P<0.05) enhances the cartilage surface, matrix, cell distribution and population viability, and subchondral bone indices. No statistical difference was observed between IPFP-ASCs+Sec and IPFP-ASCs. Conclusion: Administration of IPFP-ASCs+Sec has a therapeutic potential to treat KOA in rats. However, there is no difference in the combined administration of IPFP-ASCs and Sec with IPFP-ASCs alone.

Zinc Supplementation Reduces the Formation of Neutrophil Extracellular Traps by Decreasing the Expression of Peptidyl Arginine Deiminase 4.

SCOPE: Neutrophils play a decisive role during the immediate defense against infections. However, as observed during rheumatoid arthritis, activated neutrophils can also cause tissue damage. Previous studies indicate that zinc supplementation may alter certain neutrophil functions. However, precise underlying mechanisms and possible effects of zinc deficiency remain incompletely understood. The objective of this study is to investigate the effects of changes in zinc status on formation of neutrophil extracellular traps (NETs) and other fundamental neutrophil functions. METHODS AND RESULTS: Interleukin (IL)-17 and tumor necrosis factor (TNF)-α are used to simulate the inflammatory environment observed in autoimmune diseases. The study analyzes the impact of the zinc status on NETs release, using a fluorescence plate reader, and on the expression of peptidylarginine deiminase 4 (PAD4), S100A8/A9, and certain cytokines by PCR and western blot. These results show that zinc supplementation significantly reduces NETs formation and downregulates PAD4 protein expression. Zinc supplementation results in increased protein expression of interleukin-1 receptor antagonist (IL-1RA) and IL-8 in stimulated cells. CONCLUSION: The results suggest that changes in extracellular zinc availability may influence the functions of neutrophils. Therefore, maintaining an appropriate zinc level is advisable for preserving innate immunity and to prevent hyper-activation of neutrophils.

Appropriate care in chronic limb threatening ischemia: A review of current evidence and outcomes.

Chronic limb threatening ischemia (CLTI) poses a significant treatment challenge for vascular surgeons, interventionalists, podiatrists, and associated medical specialists. The evidence for what constitutes appropriate care is rapidly evolving and new treatment options are in constant development. This review examines the current guidelines for CLTI care, as well as reported outcomes for multiple care strategies in this patient population, including revascularization and medical optimization. We performed a literature review of the PubMed database, reviewing articles that reported outcomes for CLTI care between 2000 and 2023, and described these outcomes as they relate to the current state of CLTI treatment. Significant data are still forthcoming regarding CLTI care, but widespread adoption of appropriate CLTI care is essential for the treatment of this vulnerable population.

Polyvinyl alcohol/soybean isolate protein composite pad with enhanced antioxidant and antimicrobial properties induced by novel ternary nanoparticles for fresh pork preservation.

In this study, oregano essential oil (OEO)-loaded soluble soybean polysaccharide (SSPS) -nisin nanoparticles (ONSNPs) were formulated through electrostatic attraction-driven and hydrophobic interactions utilizing SSPS, nisin, and OEO as raw materials. ONSNPs were integrated into polyvinyl alcohol (PVA) and soybean protein isolate (SPI) matrices to create composite pads (PS-ONSNPs) by physically cross-linked using a simple freeze-thaw cycling process. The effects of ONSNPs content on the structure and physicochemical properties were evaluated. The results revealed that strong intermolecular interactions between ONSNPs and the PS matrices affected the crystallinity, microstructure, and thermal stability of the pads. Upon incorporating 5 % to 15 % ONSNPs, the structure of composite pads became denser, and the mechanical properties and water resistance were enhanced. Concurrently, the PS-ONSNPs pads facilitated the protection and controlled release of OEO. Furthermore, ONSNPs significantly improved the antioxidant activity of the pads and effectively inhibited the growth of Staphylococcus aureus and Escherichia coli. The prepared PS-ONSNPs 15 % pad was applied to storage experiments of fresh pork, which could extend the shelf life of meat to 10-12 days under 4 °C storage conditions. Therefore, the composite pad devised in this research holds promise as a viable option for intelligent active packaging of fresh meat.

Intraluminal crossing of infrainguinal SFA chronic total occlusions may offer patency superiority compared to subintimal crossing.

OBJECTIVES: Patency for chronic total occlusions (CTO) of the superficial femoral artery (SFA) after endovascular interventions traditionally demonstrate a low 1-year patency ranging from 40%-60%. The optical coherence tomography (OCT) catheter (Avinger Inc., Redwood City, CA) uses light-based technology imaging to cross Trans-Atlantic Inter-Society Consensus D (TASC D) lesions intraluminally with direct intra-arterial visualization. Insufficient data exist evaluating intraluminal crossing with OCT imaging compared with traditional subintimal techniques. We evaluated outcomes for TASC D lesions crossed intraluminally. METHODS: A retrospective analysis of patients with SFA TASC D lesions crossed intra-arterially with the OCT catheter imaging. Descriptive statistics evaluated patient characteristics which included patient demographics, Rutherford scores, ABIs, CTA information, lesion categorization, as well as runoff score. Patency at baseline, 30-day, 6-month, and 1-year outcomes were compared using t-tests. Cumulative patency rates were evaluated using Kaplan-Meier analysis. RESULTS: 101 patients underwent elective intervention for SFA TASC D lesions with the OCT catheter. The crossing rate was 78.2%, mean lesion length was 16.2 cm, and runoff at the tibial level was 2.2 patent vessels. Mean age and BMI were 64 years and 29 kg/m2, respectively. Patient characteristics are male (57%); Caucasian (90%); ever smoking (85%); hypertension (82%), hyperlipidemia (70%), and diabetes (46%). Pre-operative computed tomography demonstrated SFA lesions were predominantly eccentric (91%) with mild to moderate calcification (90%). All underwent PTA, 87% were stented (mean stent length: 186.1 mm), mean crossing time was 13.4 min. Pre-operative, 30-day, 6-month, and 1-year post-operative mean Rutherford-Becker scores were 4, 1, 1, and 1, respectively (p < 0.0001). Mean pre-operative ABI was 0.49, compared to 0.84 at 30 days, 0.64 at 6 months, and 0.67 at 1 year (p < .0001). Duplex demonstrated 6- and 12-month primary patency of 89% and 75%; primary-assisted patency was 94% and 84%. CONCLUSIONS: The OCT imaging catheter successfully crossed long chronic total occlusions of the SFA using direct intra-arterial imaging. Compared to subintimal techniques, patients had high 1-year primary patency and prolonged symptom improvement with intraluminal crossing. These data suggest that intraluminal crossing of TASC D lesions may be superior to traditional subintimal crossing techniques.

Peptidylarginine deiminase (PAD): A promising target for chronic diseases treatment.

In 1958, the presence of citrulline in the structure of the proteins was discovered for the first time. Several years later they found that Arginine converted to citrulline during a post-translational modification process by PAD enzyme. Each PAD is expressed in a certain tissue developing a series of diseases such as inflammation and cancers. Among these, PAD2 and PAD4 play a role in the development of rheumatoid arthritis (RA) by producing citrullinated autoantigens and increasing the production of inflammatory cytokines. PAD4 is also associated with the formation of NET structures and thrombosis. In the crystallographic structure, PAD has several calcium binding sites, and the active site of the enzyme consists of different amino acids. Various PAD inhibitors have been developed divided into pan-PAD and selective PAD inhibitors. F-amidine, Cl-amidine, and BB-Cl-amidine are some of pan-PAD inhibitors. AFM-30a and JBI589 are selective for PAD2 and PAD4, respectively. There is a need to evaluate the effectiveness of existing inhibitors more accurately in the coming years, as well as design and production of novel inhibitors targeting highly specific isoforms.

Hoffa's fat pad resection during total knee arthroplasty does not affect functioning and gait: a double-blind randomized clinical trial.

INTRODUCTION: Hoffa's fat pad is considered a source of anterior knee pain and may limit prosthetic knee function. Resection of Hoffa's fat pad in total knee arthroplasty (TKA), however, is controversial, and little is known about the functional outcomes including gait quality. This double-blind randomized controlled trial (i) compared functional recovery between TKAs where Hoffa was resected or preserved, and (ii) compared recovery of self-reported function with objective (gait-related) outcomes. MATERIALS AND METHODS: Eighty-five patients (age 66.4 ± 8.0 years, 47% women) scheduled to undergo TKA for primary osteoarthritis were randomly assigned to either fat pad resection or preservation. Subjective measures of functioning were assessed at baseline, 6 weeks, 3 months, and 12 months postoperatively and included the Knee Injury and Osteoarthritis Outcome Score (KOOS), Kujala, and visual analog scale (VAS) for pain. Objective measures of functioning were assessed at baseline, 3 months, and 12 months postoperatively and included instrumented range-of-motion and gait analysis. Longitudinal analyses (generalized estimating equations) were used to compare recovery between groups, and chi-square tests compared attainment of minimal clinical important difference (MCID) and patient acceptable symptom state (PASS). Finally, correlation analyses explored associations between subjective and objective recovery in function. RESULTS: Resection patients showed poorer improvement in KOOS quality of life in the first 6 weeks (B=-10.02, 95% confidence interval (CI) [-18.91, -1.12], p = .027), but stronger improvement in knee extension after 3 months (B = 3.02, 95%CI [0.45, 5.60], p = .021) compared to preservation patients. Regarding MCID or PASS, no differences were noted between groups at 3 and 12 months (all p > .05). Subjective function substantially improved in the first 3 months, while objective outcomes improved only between 3 and 12 months. Moderate to strong correlations were identified between changes in knee flexion and gait with Kujala and KOOS in the resection but not in the preservation group. CONCLUSIONS: Similar functional outcomes were achieved after TKA with or without resection of Hoffa's fat pad. Hence, removing the fat pad to promote surgical exposure will not affect functional outcomes including gait quality. Functional recovery of objective outcomes was not always consistent with subjective recovery, suggesting that both self-reported as well as objective, gait-related outcomes may provide meaningful information on functional recovery following TKA. TRIAL REGISTRATION: This clinical trial was prospectively registered under the Netherlands Trial Registry (# NL3638). This registry has recently been replaced by the Dutch Trial Registry where this study can be accessed via https://onderzoekmetmensen.nl/en/trial/20994 .

Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

OBJECTIVE: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee. METHODS: Intra-articular adipose tissue development was studied using reporter mice. Mice with selective lipodystrophy of intra-articular adipose tissue were generated by conditional knockout (cKO) of Bscl2 in Gdf5-lineage cells, and compared with whole-body Bscl2 knockout (KO) mice with generalised lipodystrophy and associated systemic metabolic dysfunction. OA was induced by surgically destabilising the medial meniscus (DMM) and obesity by high-fat diet (HFD). Gene expression was analysed by quantitative RT-PCR and tissues were analysed histologically. RESULTS: The infrapatellar fat pad (IFP), in contrast to overlying subcutaneous adipose tissue, developed from a template established from the Gdf5-expressing joint interzone during late embryogenesis, and was populated shortly after birth by adipocytes stochastically arising from Pdgfrα-expressing Gdf5-lineage progenitors. While female Bscl2 KO mice with generalised lipodystrophy developed spontaneous knee cartilage damage, Bscl2 cKO mice with intra-articular lipodystrophy did not, despite the presence of synovial hyperplasia and inflammation of the residual IFP. Furthermore, male Bscl2 cKO mice showed no worse cartilage damage after DMM. However, female Bscl2 cKO mice showed increased susceptibility to the cartilage-damaging effects of HFD-induced obesity. CONCLUSION: Our findings emphasise the prevalent role of systemic metabolic and inflammatory effects in impairing cartilage homeostasis, with a modulatory role for intra-articular adipose tissue.