Collagenase Injection Research Articles

Are neutrophil–lymphocyte and platelet–lymphocyte ratios useful for determining active phase of Peyronie’s disease?

Background: Management options for Peyronie’s disease (PD) are determined by the phase of the condition. Experts counsel against surgical intervention during the active phase of PD. Patients with chronic phase of PD are offered either collagenase injections or surgical intervention. Accurately characterising a patient’s phase of PD is crucial in determining the appropriate treatment option. Objective: To investigate neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) as possible predictors for the determination of acute or chronic phase of PD. Methods: This study retrospectively queried all patients who presented for initial diagnosis of PD from 2016 to 2020 and had complete blood count (CBC) laboratory values before initial therapy. PD phase was defined per the American Urological Association guidelines. The active phase of PD was defined as a changing penile curvature and/or growing palpable plaque. The chronic phase of PD was defined as a stabilised penile curvature. All statistical analyses were two-tailed, using a significance level of 0.05. Results: One hundred nine patients met inclusion: 27 (25%) active phase and 82 (75%) chronic phase patients. Demographic and erectile characteristics were not statistically different between the two groups. NLR and PLR values between active and chronic phase patients were comparable ( p > 0.05). A linear regression evaluated correlations between the duration of PD and either NLR or PLR. Neither NLR nor PLR was correlated with PD duration on Spearman, Pearson, or Kandall tests. In addition, NLR and PLR were not noted to be predictors of PD phase on multiple logistic regression. Finally, a receiver operator characteristic curve was generated. NLR and PLR yielded an area under curve of 58% and 57.8%, respectively. Conclusions: Two recent studies suggested NLR and PLR could be used to predict the phases of PD. However, after evaluating a cohort of 109 men from our institution, our data do not support the use of peripheral blood PLR or NLR to determine the phase of PD.

A 12-Year Review of Clinical Practice Patterns in Dupuytren Contracture Based on Continuous Certification by the American Board of Plastic Surgery.

The American Board of Plastic Surgery collects data on 20 common plastic surgery operations as part of the Continuous Certification process. The goal of this study was to describe clinical trends in Dupuytren contracture repair since 2008 as they relate to evidence-based medicine articles published in this timeframe. Cumulative tracer data for Dupuytren contracture were reviewed for the period from February of 2008 to March of 2020 and compared with evidence-based medicine articles published in Plastic and Reconstructive Surgery . Topics were categorized as (1) pearls, addressed in both the tracer data and evidence-based medicine articles, (2) topics only addressed in tracer data, and (3) topics only addressed in evidence-based medicine articles. As of March of 2020, 230 cases of Dupuytren contracture had been entered. The median age at time of surgery was 65 years (range, 38 to 91 years). Practice patterns from 2008 through 2014 were compared with those between 2015 and 2020. The most common surgical technique was limited fasciectomy (62 percent of cases). Differences in practice between these time periods included decrease in the use of radical fasciectomy (34 percent versus 16 percent, p = 0.002), increase in percutaneous cordotomy (0 percent versus 13 percent), and increase in the use of collagenase injections (0 percent versus 9 percent, p = 0.001). Use of Bier blocks increased (1 percent versus 7 percent), and tourniquet use decreased (97 percent versus 80 percent). Significant changes were also noted in postoperative management. By examining American Board of Plastic Surgery tracer data, the authors have described national trends in presentation and surgical techniques for Dupuytren contracture repair over a 14-year period.

Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage.

Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH. Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes. VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.

CM-352 Efficacy in a Mouse Model of Anticoagulant-Associated Intracranial Hemorrhage.

Background Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 −/− mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 −/− mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.

A systematic review of modeling in Peyronie's Disease

ABSTRACT Introduction Penile modeling to correct the penile curvature in Peyronie's disease (PD) may be achieved manually (intra-operatively or post-injection) or by using assisted devices (penile traction, vacuum device or penile prosthesis). To the best of our knowledge this is the first systematic review of the literature comprehensively evaluating penile modeling procedures. Objective To evaluate the efficacy, safety and satisfaction associated with penile modeling in patients with PD. Methods A PROSPERO registered (CRD42021241729) systematic search in MEDLINE and Cochrane Library was done in accordance with PRISMA. PICO: Studies were deemed eligible if they assessed patients with PD (P) undergoing modeling procedures (I) with or without comparative group(C) evaluating the efficacy, safety or patient satisfaction (O). Results A total of 23 studies, involving 1,238 patients were included in the systematic review. The majority (n=13) studied penile traction therapy and the least being manual modeling at home and manual modeling after collagenase injection (1 each). The studies were of low and intermediate quality (mean Newcastle-Ottawa Scale score of 5.7 and mean Jadad score of 3.3) with a mean level of evidence of 3.4. The mean penile curvature at baseline was between 31 and 80.8 degrees. Nine (39.1%) studies found a significant improvement (p&amp;lt;0.05) of penile curvature after penile modeling, ranging between 11.7 and 37.2 degrees. A increase in mean stretched penile length was reported in 7 (30.4%) articles, varying between 0.4 and 1.8 cm. Serious complications such as penile prosthesis malfunctions (3.3%-11.1%) and urethral injuries (2.9%) were only reported for intra-operative manual modeling. Conclusion Although individual studies have noted improvement in penile curvature and stretched penile length, specific recommendations regarding penile modeling in PD cannot be provided due to the inability to perform a pooled analysis of the included studies with significant heterogeneity and the absence of standardized methods to report complications and patient satisfaction. Further RCTs with adequate sample size, validated assessment tools and longer follow-up are needed. Disclosure Work supported by industry: no. A consultant, employee (part time or full time) or shareholder is among the authors (Boston Scientific).

Palmitoylethanolamide ameliorates neuroinflammation via modulating PPAR-α to promote the functional outcome after intracerebral hemorrhage

Intracerebral hemorrhage is a type of acute cerebrovascular disease that remains one of the main causes of death and disability. After the onset of ICH, different types of severe pathophysiological changes can cause great damage to brain tissue, including neuroinflammation. Our study demonstrated the effect of PEA on modulating microglia phenotype and neuroinflammation, as well as the possible underlying mechanisms after ICH for the first time. The phenotypic transformation of microglia and simulation of neuroinflammation after ICH in vitro was induced by hemoglobin on BV2 cells. Additionally, the experiment in vivo model was induced by collagenase injection in mice. The role of PEA on hematoma clearance was also discussed. Western blot, ELISA and immunofluorescence staining were used to determine the phenotypic polarization of microglia and neuroinflammation. In order to evaluate the role of PPAR-α in the anti-inflammatory effect of PEA after ICH, the PPAR-α antagonist GW6471 was utilized. Behavior tests examined the effect of PEA on improving neuronal function. Our results showed that PEA can ameliorate neuroinflammation by inhibiting upregulation of NF-κB, IL-1β and TNF-α, both in vivo and in vitro. Additionally, PEA can improve motor function in ICH mice and promotes hematoma clearance. At the same time, PEA can increase the levels of PPAR-α in the nucleus. Hence, PPAR-α antagonists can reverse the protective effects of PEA on neuroinflammation. These results suggest that PEA is involved in microglia polarization, attenuating the activation of neuroinflammation, as well as improving motor function after ICH. This, at least in part, may contribute to the involvement of PPAR-α modulation of NF-κB.

Intraventricular hemorrhage induces inflammatory brain damage with blood-brain barrier dysfunction in immature rats.

We aimed to characterize a preclinical model of intraventricular hemorrhage-induced brain damage (IVH-BD) in extremely low birth weight newborns (ELBWN), to identify potential therapeutic targets based on its pathophysiology. IVH was induced in 1-day-old (P1) Wistar rats by left periventricular injection of clostridium collagenase (PVCC). At P6, P14, and P45 IVH-BD (area of damage, motor and cognitive deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: ipsilateral hemisphere and corpus callosum atrophy, oligodendroglial population and myelin basic protein signal reduction), blood-brain barrier (BBB) dysfunction (occludin and Mfsd2a expression, Gadolinium leakage) and inflammation (TNFα, TLR4, NFkB, and MMP9 expression; immune cell infiltration), excitotoxicity (Glutamate/N-acetylaspartate), and oxidative stress (protein nitrosylation) were assessed. Sham animals were similarly studied. IVH-BD leads to long-term WMI, resulting in motor and cognitive impairment, thus reproducing IVH-BD features in ELBWN. BBB dysfunction with increased permeability was observed at P6 and P14, coincident with an increased inflammatory response with TLR4 overexpression, increased TNFα production, and increased immune cell infiltration, as well as increased excitotoxicity and oxidative stress. This model reproduced some key hallmarks of IVH-BD in ELBWN. Inflammation associated with BBB dysfunction appears as relevant therapeutic target to prevent IVH-BD-induced WMI. Paraventricular injection of clostridium collagenase (PVCC) to 1-day-old Wistar rats uniquely reproduced the neuroimaging, histologic and functional characteristics of intraventricular hemorrhage-induced brain damage (IVH-BD) in extremely low birth weight newborns (ELBWN). PVCC-induced IVH triggered a prolonged inflammatory response associated with blood-brain barrier increased permeability, which in turn facilitates the infiltration of inflammatory cells. Thus, PVCC led to white matter injury (WMI) resulting in long-term motor and cognitive impairment. This model offers a valuable tool to obtain further insight into the mechanisms of IVH-BD in ELBWN and proposes some key therapeutic targets.

Activation of P2X4 receptor exacerbates acute brain injury after intracerebral hemorrhage.

IntroductionIntracerebral hemorrhage (ICH) accounts for 10%–15% of all strokes and culminates in high mortality and disability. After ICH, brain injury is initiated by the mass effect of hematoma, followed by secondary cytotoxic injury from dying brain cells, hematoma disintegration, and cascading brain immune response. However, the molecular mechanism of secondary cytotoxic brain injury in ICH is not completely understood. The sensitive purinergic receptor, P2X4 receptor (P2X4R), was known to recognize extracellular free ATP released by dying cells during tissue injury.AimsIn this study, we aim to understand the role of P2X4R in acute brain injury triggered by ICH.ResultsIn this study, we found that the sensitive purinergic receptor, P2X4R, was upregulated in the brain of patients with ICH as well as in a mouse model of ICH induced by collagenase injection. P2X4R blockage with the specific inhibitor 5‐BDBD attenuated brain injury in ICH mice by significantly reducing brain edema, blood–brain barrier leakage, neural death, and ultimately acute neurodeficits. Further study indicated that the protective effect of P2X4R inhibition is related to decreased pro‐inflammatory activity of microglia and recruitment of peripheral immune cells into the hemorrhagic brain.ConclusionsThese results suggest that the P2X4 receptor is activated by ICH stimuli which worsen brain injury following ICH.

Effect of nanoparticle-mediated delivery of SFRP4 siRNA for treating Dupuytren disease.

Dupuytren disease (DD) is a progressive fibrous proliferative disease. It invades the palmar aponeurosis and extends to the finger fascia, eventually leading to flexion contracture of the metacarpophalangeal or interphalangeal joint. At present, surgical resection and the local injection of collagenase are the main methods for the treatment of DD, but postoperative complications and high recurrence rates often occur. Bioinformatics analysis showed that the increased expression of SFRP4 protein was closely related to the incidence of DD. Persistent and effective inhibition of SFRP4 expression may be a promising treatment for DD. We prepared SFRP4 siRNA/nanoparticle complexes (si-SFRP4) and negative siRNA/nanoparticle complexes (NC) and applied them in vitro and in vivo. Flow cytometry analysis showed that si-SFRP4 could be successfully transfected into DD cells. MTT and EdU staining assays showed that the OD values and percentage of EdU-positive cells in the si-SFRP4 group were significantly lower than those in the NC group. Scratch tests showed that the wound healing rate of the si-SFRP4 group was lower than that of the NC group, and the difference was statistically significant. The expression of SFRP4 and α-SMA protein in the si-SFRP4 group significantly decreased in both DD cells and xenografts. Compared with the NC group, the xenograft quality of the si-SFRP4 group was significantly reduced. Masson's trichrome staining showed that the collagen and fibrous cells in the si-SFRP4 group were more uniform, slender, parallel and regular. The above experimental results suggest that the proliferation and metabolism of palmar aponeurosis cells and the quality of metacarpal fascia xenografts were both significantly decreased. We speculated that nanoparticle-mediated SFRP4 siRNA can be used as a potential new method for the treatment of DD.

A Role of Complement in the Pathogenic Sequelae of Mouse Neonatal Germinal Matrix Hemorrhage.

Germinal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia, and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed and characterized a mouse model of GMH based on the injection of collagenase into the subventricular zone of post-natal pups and utilized the model to investigate the role of complement in PHH development. The site-targeted complement inhibitor CR2Crry, which binds deposited C3 complement activation products, localized specifically in the brain following its systemic administration after GMH. Compared to vehicle, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Complement inhibition also improved survival and weight gain, and it improved motor performance and cognitive outcomes measured in adolescence. The progression to PHH, neuronal loss, and associated behavioral deficits was linked to the microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Thus, complement plays an important role in the pathological sequelae of GMH, and complement inhibition represents a novel therapeutic approach to reduce the disease progression of a condition for which there is currently no treatment outside of surgical intervention.

Patients’ perspectives of collagenase injection or needle fasciotomy and rehabilitation for Dupuytren disease, including hand function and occupational performance

Purpose To describe patients’ perspectives of collagenase injection or needle fasciotomy for Dupuytren disease (DD) including hand therapy, and their view of hand function and occupational performance. Materials and methods Interviews were performed with twelve patients who had undergone non-surgical treatment and rehabilitation for DD. Data was analysed using a problem-driven content analysis using the model of Patient Evaluation Process as a theoretical framework. Results The participants' previous experiences influenced their expectations of the upcoming treatment and they needed information to be prepared for treatment. Treatment and rehabilitation had a positive impact on daily life and were regarded as effective and simple with quick recovery. However, there could be remaining issues with tenderness or stiffness. The participants expressed their belief in rehabilitation and how their own efforts could contribute to an improved result. Despite concerns about future recurrence participants described increased knowledge and sense of control regarding future needs. Conclusion Undergoing a non-surgical treatment and rehabilitation process for DD was regarded as quick and easy and can meet the need for improved hand function and occupational performance. Taking responsibility for one’s own rehabilitation was considered to influence the outcome positively. The theoretical framework optimally supported the exploration of participants’ perspective. Implications for rehabilitation Treatment of Dupuytren Disease (DD) with needle/collagenase combined with hand therapy was experienced as giving fast improvement in hand function and occupational performance. An individualized care process which satisfies the need for knowledge about the disease, prognosis, treatment options and rehabilitation can give individuals suffering from DD a sense of security. The need for active participation in the DD care process can vary and it is crucial to listen to individuals’ opinions and needs. Individuals can take considerable responsibility for rehabilitation after non-surgical treatment for DD and regard it as important for the outcome.

Attenuation of osteoarthritis progression through intra-articular injection of a combination of synovial membrane-derived MSCs (SMMSCs), platelet-rich plasma (PRP) and conditioned medium (secretome)

PurposeOsteoarthritis (OA) as a progressive destructive disease of articular cartilage is the most common joint disease characterized by reduction of joint cartilage thickness, demolition of cartilage surface and new bone formation. To overcome these problems, the purpose of the current research was to evaluate and compare the in vivo effects of synovial membrane-derived mesenchymal stem cell (SMMSCs), platelet-rich plasma (PRP) and conditioned medium (secretome) on collagenase II-induced rat knee osteoarthritis (KOA) remedy.MethodsFor the first step, SMMSCs were isolated and characterized. Also, secretome was collected from SMMSCs culture. Furthermore, PRP was collect from the rat heart venous blood. Second, two injection of collagenase II with an interval of 3 days was performed in the knee intra-articular space to induce osteoarthritis. Two weeks later, animals were randomly divided into 6 groups. Control group without treatment, positive group: taken an intra-articular sodium hyaluronate injection (0.1 ml), treatment groups taken an intra-articular injection of; treatment 1: SMMSCs (5 × 106), treatment 2: SMMSCs (5 × 106)/secretome (50 µl), treatment 3: SMMSCs (5 × 106)/PRP (50 µl), and treatment 4: SMMSCs (5 × 106)/ secretome (50 µl)/ PRP (50 µl). Three months later, rats were killed and the following assessments were executed: radiography, histopathology, and immunohistochemistry.ResultsOur findings represented that a combination of the SMMSCs/secretome/PRP had a considerable effect on glycosaminoglycans (GAGs) and collagen II contents, articular cartilage preservation, compared with other groups. In addition, combination of the SMMSCs with PRP and secretome showed the lowest expression of mmp3, while SOX9 had the highest expression in comparison with other groups. Also, SMMSCs-injected groups demonstrated better results compared with positive and control groups.ConclusionsInjecting a combination of the SMMSCs/secretome/PRP resulted in better efficacy in terms of joint space width, articular cartilage surface continuity and integrity, sub-chondral bone and ECM constituents such as collagen II. Indeed, transplantation of this combination could be considered as a preliminary therapy for clinical trial study in the future.

"Extremely Painful, but Worth It": The Lived Experience of Receiving Collagenase as Treatment for Dupuytren Disease.

Collagenase injection is a relatively new, minimally invasive treatment option for Dupuytren disease. Most literature focusses on quantitative outcome measures, such as degree of residual contracture and recurrence. The patient experience of the treatment has rarely been explored. This study sought to explore patients' experiences of the treatment process, including their reasons for seeking and choosing the treatment. A qualitative descriptive design was used to explore patients' experiences. Seven patients (aged 57 to 81 years) who had received collagenase treatment for Dupuytren disease engaged in individual, semistructured interviews. Interviews were audio recorded, transcribed verbatim, and analyzed thematically. Thematic analysis revealed that Dupuytren disease was an obstacle to doing things, but not a barrier. Patients "went with the flow" of treatment, often taking a passive approach to their health care decisions. Patients found the collagenase injections to be extremely painful, but worth it. They had a varied knowledge of the disease and treatment. Patients were pleased with the results of the collagenase treatment, even if the finger was not completely straight or there was recurrence. The quick recovery and minimal complications were positive factors; however, the injections were extremely painful and could deter patients from future treatment. This research highlighted that a number of patients had low health literacy regarding their condition, and this affected their expectations of treatment outcomes and future treatment seeking. There are opportunities for health professionals to improve health literacy for people with Dupuytren disease, possibly in a group setting.

Restorative and pain-relieving effects of fibroin in preclinical models of tendinopathy

The term tendinopathy indicates a wide spectrum of conditions characterized by alterations in tendon tissue homeostatic response and damage to the extracellular matrix. The current pharmacological approach involves the use of nonsteroidal anti-inflammatory drugs and corticosteroids often with unsatisfactory results, making essential the identification of new treatments. In this study, the pro-regenerative and protective effects of an aqueous fibroin solution (0.5–500 μg/mL) against glucose oxidase (GOx)-induced damage in rat tenocytes were investigated. Then, fibroin anti-hyperalgesic and protective actions were evaluated in two models of tendinopathy induced in rats by collagenase or carrageenan injection, respectively. In vitro, 5–10 μg/mL fibroin per se increased cell viability and reverted the morphological alterations caused by GOx (0.1 U/mL). Fibroin 10 μg/mL evoked proliferative signaling upregulating the expression of decorin, scleraxin, tenomodulin (p < 0.001), FGF-2, and tenascin-C (p < 0.01) genes. Fibroin enhanced the basal FGF-2 and MMP-9 protein concentrations and prevented their GOx-mediated decrease. Furthermore, fibroin positively modulated the production of collagen type I. In vivo, the peri-tendinous injection of fibroin (5 mg) reduced the development of spontaneous pain and hypersensitivity (p < 0.01) induced by the intra-tendinous injection of collagenase; the efficacy was comparable to that of triamcinolone. The pain-relieving action of fibroin (peri-tendinous) was confirmed in the model of tendinopathy induced by carrageenan (intra-tendinous) where this fibrous protein was also able to improve tendon matrix organization, normalizing the orientation of collagen fibers. In conclusion, the use of fibroin in tendinopathies is suggested taking advantage of its excellent mechanical properties, pain-relieving effects, and ability to promote tissue regeneration processes.

Collagenase and the Treatment of Dupuytren Contracture: Efficacy of Treatment and Patient Satisfaction.

Background: Collagenase clostridium histolyticum has become a widely used treatment in the management of Dupuytren disease. The aims of this study are to assess the immediate success of treatment of Dupuytren contracture with collagenase injection, to measure long-term patient-rated outcomes, to determine whether the risk factors for the disease impacted outcomes and to report complications of collagenase treatment. Methods: A prospective study was performed in a tertiary referral centre. Measurements were recorded pre-treatment, day 1 and day 90. Patient-rated outcome scores were measured using Disability of the Arm, Shoulder and Hand questionnaire (DASH) and the Michigan Hand Questionnaire (MHQ) at minimum 36 months post-injection. Results: The study included 45 patients with 53 hands with a mean age of 65.7 years. The treatment was successful in 62% of patients with the greatest improvement in the metacarpal-phalangeal joint of the little finger. Diabetes, epilepsy, gender, alcohol intake and positive family history had no statistically significant predictive value on successful outcomes. Patient satisfaction at 41 months was high with mean MHQ score of 97.3. Conclusions: Collagenase is effective in the treatment of Dupuytren contracture, with disease involving the little finger showing the greatest benefit. Risk factors for development of Dupuytren disease had no effect on successful outcome and long-term satisfaction rates are high. Level of Evidence: Level III (Therapeutic).

Abstract 98: Brain-Derived Programmed Death-Ligand 1 Induces Post-Stroke Immunosuppression

Background and purpose: Post-stroke immunosuppression is associated with increased infection risk and mortality of stroke patients. However, the mechanisms driving post-stroke immunosuppression are not fully elucidated and strategies to prevent this fatal complication are lacking. We investigated the role of programmed death-ligand 1 (PD-L1) on post-stroke lymphocyte deficiency in a murine model of intracerebral hemorrhage (ICH). Methods: ICH was induced by intracerebral injection of autologous blood or collagenase IV to male C57BL/6 (B6) mice. Mice were randomly assigned into two groups to received anti-PD-1 antibody and vehicle respectively via intraperitoneal injection operating at 1 hour after ICH. Neurological function assessment, immunofluorescence, Elisa, flow cytometry, lung colony calculated were analyzed. Results: In a mice model of ICH, we identified that neuron-derived programmed death ligand 1 (PD-L1) are downregulated and released to the blood post ICH. Increased PD-L1 induced T cell and NK cell deficiency via their expressed PD-1, which are associated with increased lung infection post-ICH. Blocking PD-L1 pathway via an anti-PD-1 monoclonal antibody prevented the spleen atrophy of ICH mice, and improved peripheral T and NK cell numbers and function. Anti PD-1 antibody treated mice showed improved clinical outcome and reduced pulmonary bacterial burden. Conclusions: This study identified brain-derived PD-L1 to the periphery as a new pathway that lead to post-stroke immunosuppression, targeting PD-L1 could be a potential treatment strategy to reduce post-stroke infection risk. Key words: Programmed death ligand 1,intracerebral hemorrhage, neuron,immunosuppression, inflammation Short title: PD-L1 and post-stroke immunosuppression

Abstract WP141: Effect Of Non-invasive Vagus Nerve Stimulation In Hemorrhagic Brain Injury And Permanent Ischemic Stroke In Rats

Introduction: Non-invasive vagus nerve stimulation (nVNS) reduces infarct volume after transient ischemia in rats. Here, we tested the effect of nVNS in intracerebral hemorrhage (ICH) and permanent ischemic brain injury models. Methods: ICH was induced by whole blood (n=24) or collagenase (n=24) injection into the striatum of adult male and female Wistar rats. 1-hour sham stimulation (n=16) or nVNS (n=32) was initiated 30 minutes after injection. Spontaneous circling, hindlimb retraction, and grasp ability were tested at 24 hours to measure functional deficit. Rats were euthanized 24 hours or one week after injury, and brain tissue was processed for water content analysis (n=24) and histology (n=24), respectively. Permanent ischemia was induced by filament occlusion of the right middle cerebral artery in adult male Wistar rats (n=18). Sham stimulation and nVNS initiated 30 minutes after the induction of ischemia were applied for 1 hour and 3 hours (n=6 per group). Rats were euthanized 24 hours later to measure infarct volume. Results: 1-hour nVNS was associated with a non-significant reduction in hematoma volume in both models of ICH (Fig). Animals treated with nVNS demonstrated better functional outcome at 24 hours after ICH ( p =0.042). There was no difference in brain edema between control and active treatment arms in both models of ICH. 3-hour nVNS reduced infarct volume by 21% in permanent ischemia ( p =0.047, Fig). Conclusion: The results of this study support prior evidence that nVNS may have a therapeutic potential in ischemic stroke. nVNS is currently being evaluated in two clinical studies (NCT03733431 and NCT04050501) for the treatment of acute ischemic stroke. The lack of adverse events in two different models of ICH in this study suggests that nVNS could be safely administered as early as an ambulatory setting before the stroke etiology (ischemic vs. hemorrhagic) has been determined.

Abstract WP142: T Cells Aggravate Intracerebral Hemorrhage Injury

Intracerebral hemorrhage (ICH), a devastating form of stroke, has a mortality of 40% and no available treatment. Inflammation contributes to the genesis and expansion of perihematomal edema (PHE) in ICH, thus driving secondary injury and subsequent neurological deterioration. This study was carried out to elucidate contributions of lymphocytes, specifically CD4 + cells in the formation of PHE and ICH-induced neural injury. Upon examination of brain sections of ICH patients, we observed abundant CD4 + T cells among the PHE-infiltrating immune cells as early as 24 hours post-ictus. Analogous findings in ICH mouse model induced with autologous blood or collagenase injection confirmed the phenomenon. Using anti-CD4 antibody to deplete CD4 + T cells, we find that brain-infiltrating CD4 + T cells exacerbates acute ICH injury in mice by reducing BBB integrity and promoting leukocytes recruitment with early and time-dependent CD4 + T cells activation. Brain infiltrating CD4 + T cells exhibit activated transcriptome signatures, promoting local inflammation via IL-17. In the hemorrhagic brain, CD4 + T cells induces CD31 + endothelial cell apoptosis via death receptor-ligands TRAIL-DR5 pathway; specific ablation of CD4 + T cells with depleting antibody results in reduced PHE volume and improved long-term neurological outcome. In all, these data sheds new lights on T cell-mediated immune responses contributing to PHE and brain injury in ICH.

Treatment Options for Dupuytren's Disease: Tips and Tricks.

Background:Dupuytren's disease (DD) is a common fibroproliferative condition of the hand.Methods:Management of DD includes observation, non-operative management, and operative management. Operative treatments include percutaneous needle fasciotomy (PNF), open fasciotomy (OF), Clostridium collagenase histolyticum (CCH) injections, limited fasciectomy (LF) and dermofasciectomy (DF). The various methods of DD treatment are reviewed.Results:We summarize the highlights of each treatment option as well as the strengths and weaknesses. PNF has an immediate improvement, but a higher recurrence rate, potential problematic skin tears, and rare tendon or nerve complications. Limited fasciectomy removes the thickened, diseased tissue but has a more prolonged recovery and has a higher rate of significant complications. Dermofasciectomy has the highest complication rate, and the lowest recurrence. Also, secondary fasciectomy after a previous dermofasciectomy has an unexpected amputation rate as high as 8%. Collagenase injections require two visits, have an increased number of minor side effects such as skin tears, and have rare but significant side effects such as tendon rupture.Conclusions:This article gives an overview of different treatment options for DD and each of their strengths and weaknesses and provides procedural tips.

Intra-articular injection of triamcinolone acetonide sustains macrophage levels and aggravates osteophytosis during degenerative joint disease in mice.

Background and purposeCorticosteroids such as triamcinolone acetonide (TAA) are potent drugs administered intra‐articularly as an anti‐inflammatory therapy to relieve pain associated with osteoarthritis (OA). However, the ability of early TAA intervention to mitigate OA progression and modulate immune cell subsets remains unclear. Here, we sought to understand the effect of early intra‐articular injection of TAA on OA progression, local macrophages, and peripheral blood monocytes.Experimental approachDegenerative joint disease was induced by intra‐articular injection of collagenase into the knee joint of male C57BL/6 mice. After 1 week, TAA or saline was injected intra‐articularly. Blood was taken throughout the study to analyse monocyte subsets. Mice were killed at days 14 and 56 post‐induction of collagenase‐induced OA (CiOA) to examine synovial macrophages and structural OA features.Key resultsThe percentage of macrophages relative to total live cells present within knee joints was increased in collagenase‐ compared with saline‐injected knees at day 14 and was not altered by TAA treatment. However, at day 56, post‐induction of CiOA, TAA‐treated knees had increased levels of macrophages compared with the knees of untreated CiOA‐mice. The distribution of monocyte subsets present in peripheral blood was not altered by TAA treatment during the development of CiOA. Osteophyte maturation was increased in TAA‐injected knees at day 56.Conclusion and implicationsIntra‐articular injection of TAA increases long‐term synovial macrophage numbers and osteophytosis. Our findings suggest that TAA accentuates the progression of osteoarthritis‐associated features when applied to an acutely inflamed knee.