Golden Hour Intravenous Thrombolysis for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVES: The benefits of intravenous thrombolysis are time-dependent, with maximum efficacy when administered within the first "golden" hour after onset. Nevertheless, the impact of golden hour thrombolysis has not been well quantified. METHODS: Medline, Embase, and Web of Science databases were systematically searched from inception to August 27, 2023. We included studies that reported safety and efficacy outcomes of ischemic stroke patients treated with intravenous thrombolysis in the golden hour versus later treatment window. The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale score of 0-1 at 90 days. The secondary efficacy outcome was a good functional outcome (defined as modified Rankin Scale score of 0-2). The main safety outcome was symptomatic intracerebral hemorrhage. RESULTS: Seven studies involving 78,826 patients met the selection criteria. Golden hour thrombolysis was associated with higher odds of 90-day excellent functional outcomes (OR 1.40, 95% CI 1.16-1.67) and 90-day good functional outcomes (OR 1.38, 95% CI 1.13-1.69) compared with thrombolysis outside the golden hour. The number needed to treat to benefit for golden hour thrombolysis to reduce disability by at least 1 level on the modified Rankin Scale per patient was 2.6. Rates of symptomatic intracerebral hemorrhage and mortality were similar between groups. INTERPRETATION: Golden hour thrombolysis significantly improved acute ischemic stroke outcomes. The findings provide rationale for intensive efforts aimed at expediting thrombolytic therapy within the golden hour window following the onset of acute ischemic stroke. ANN NEUROL 2024;96:582-590.

The natural anticoagulant protein S; hemostatic functions and deficiency.

Protein S (PS) is a vital endogenous anticoagulant. It plays a crucial role in regulating coagulation by acting as a cofactor for the activated protein C (APC) and tissue factor pathway inhibitor (TFPI) pathways. Additionally, it possesses direct anticoagulant properties by impeding the intrinsic tenase and prothrombinase complexes. Protein S oversees the coagulation process in both the initiation and propagation stages through these roles. The significance of protein S in regulating blood clotting can be inferred from the significant correlation between deficits in protein S and an elevated susceptibility to venous thrombosis. This is likely because activated protein C and tissue factor pathway inhibitor exhibit low efficacy as anticoagulants when no cofactors exist. The precise biochemical mechanisms underlying the roles of protein S cofactors have yet to be fully elucidated. Nevertheless, recent scientific breakthroughs have significantly enhanced comprehension findings for these functions. The diagnosis of protein S deficiency, both from a technical and genetic standpoint, is still a subject of debate due to the complex structural characteristics of the condition. This paper will provide an in-depth review of the molecular structure of protein S and its hemostatic effects. Furthermore, we shall address the insufficiency of protein S and its methods of diagnosis and treatment.

What is the purpose of this summary? To provide an in-depth review of the molecular structure of protein S and its hemostatic effects.To address the deficiency of protein S and its methods of diagnosis and treatment.What is known? Protein S operates as an anticoagulant through its roles as a cofactor for APC, TFPI, and an inhibitor of FIXa.Protein S deficiency can be either inherited or acquired.What is new? Plasma protein S and platelet-derived protein S contribute to regulating coagulation and maintaining hemostasis. Protein S can be used as a potential promising treatment target for persons diagnosed with hemophilia.

Endoscopic repair of nasal septal perforation with anterior ethmoidal artery flap using tunnel technique.

PURPOSE: Septal perforations (SPs) present a distinct challenge. There are many described surgical approaches with variable success rates. The goal of this study is to describe a new technique in repairing SP. METHODS: A case series of eighteen patients with anterior septal perforation who underwent endoscopic repair with the "tunnel technique" based on anterior ethmoid artery flap (AEA) were analyzed. Demographic data, etiology, size of perforation, and success rate were collected. RESULTS: Eighteen cases with male predominance (67%) were enrolled from 2019 to 2022. The average perforation size was 1.5 cm (0.5- 3.6 cm). The success rate of complete SP closure was 94% (n = 17/18) with no complications after surgery. The patients were followed up for 7 ± 5.2 months. CONCLUSIONS: AEA flap reconstruction with the tunnel technique is associated with favorable outcomes in SP closure. The tunnel technique provides a useful flap bolster and minimizes the use of other supportive measures. This technique offers an addition to other techniques for septal perforation repair. LEVEL OF EVIDENCE: Level 4.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

Quasi-phase matching using frozen waves without periodic poling.

In this article, we show that quasi-phase matching can be accomplished by manipulating one of the pump beams without any periodic poling. We analyze a simple case wherein one of the interacting beams has a periodic pattern, and the others are assumed to be planewaves. We present comparisons of the efficiency of some nonlinear processes with quasi-phase matching achieved through our method and the conventional method. We demonstrate that some patterns of the pump beam can be more efficient than conventional periodic poling.

An overview on human exposure, toxicity, solid-phase microextraction and adsorptive removal of perfluoroalkyl carboxylic acids (PFCAs) from water matrices.

Perfluoroalkyl carboxylic acids (PFCAs) are sub-class of perfluoroalkyl substances commonly detected in water matrices. They are persistent in the environment, hence highly toxic to living organisms. Their occurrence at trace amount, complex nature and prone to matrix interference make their extraction and detection a challenge. This study consolidates current advancements in solid-phase extraction (SPE) techniques for the trace-level analysis of PFCAs from water matrices. The advantages of the methods in terms of ease of applications, low-cost, robustness, low solvents consumption, high pre-concentration factors, better extraction efficiency, good selectivity and recovery of the analytes have been emphasized. The article also demonstrated effectiveness of some porous materials for the adsorptive removal of the PFCAs from the water matrices. Mechanisms of the SPE/adsorption techniques have been discussed. The success and limitations of the processes have been elucidated.

A Review of the Characteristics of Clinical Trials and Potential Medications for Alcohol Dependence: Data Analysis from ClinicalTrials.gov.

Objective. This study provides a comprehensive analysis of the characteristics of clinical trials related to alcohol dependence that are registered on ClinicalTrials.gov. Methods. All ClinicalTrials.gov trials registered up to 1 January 2023 were examined, focusing on trials that involved alcohol dependence. All 1295 trials were summarized by presenting their characteristics and results and reviewed most intervention drugs used in the treatment of alcohol dependence. Results. The study analysis identified a total of 1295 clinical trials registered on ClinicalTrials.gov that were focused on alcohol dependence. Of these, 766 trials had been completed, representing 59.15% of the total, while 230 trials were currently recruiting participants, accounting for 17.76% of the total. None of the trials had yet been approved for marketing. The majority of the studies included in this analysis were interventional studies (1145 trials, or 88.41%), which accounted for most of the patients enrolled in the trials. In contrast, observational studies represented only a small portion of the trials (150 studies, or 11.58%) and involved a smaller number of patients. In terms of geographic distribution, the majority of registered studies were located in North America (876 studies, or 67.64%), while only a small number of studies were registered in South America (7 studies, or 0.54%). Conclusions. The purpose of this review is to provide a basis for the treatment of alcohol dependence and prevention of its onset through an overview of clinical trials registered at ClinicalTrials.gov. It also offers essential information for future research to guide future studies.

Resveratrol Ameliorates Vancomycin-Induced Testicular Dysfunction in Male Rats.

Background and Objectives: Numerous studies have indicated that antibiotics may adversely affect testicular and sperm function. As an alternative to penicillin, vancomycin is a glycopeptide antibiotic developed to treat resistant strains of Staphylococcus aureus. A few studies have suggested that vancomycin could cause testicular toxicity and apoptosis. Vancomycin, however, has not been investigated in terms of its mechanism of causing testicular toxicity. Materials and Methods: An experiment was conducted to investigate the effects of resveratrol (20 mg/kg, oral gavage) against vancomycin (200 mg/kg, i.p.) on the testicular function of Wistar rats for one week (7 days). There were three subgroups of animals. First, saline (i.p.) was administered to the control group. Then, in the second group, vancomycin was administered. Finally, vancomycin and resveratrol were administered in combination in the third group. Results: After seven days of vancomycin treatment, testosterone levels, sperm counts, and sperm motility were significantly reduced, but resveratrol attenuated the effects of vancomycin and restored the testosterone levels, sperm counts, and sperm motility to normal. In the presence of resveratrol, the vancomycin effects were attenuated, and the luteinizing hormone and follicular hormone levels were normalized after seven days of treatment with vancomycin. Histologically, vancomycin administration for seven days caused damage to testicular tissues and reduced the thickness of the basal lamina. However, the resveratrol administration with vancomycin prevented vancomycin's toxic effects on testicular tissue. Conclusion: Resveratrol showed potential protective effects against vancomycin-induced testicular toxicity in Wistar rats.

Evaluation of Pharmacology and Pathophysiology Knowledge of Epilepsy among Senior Pharmacy Students: A Single Center Experience.

Background and Objectives: Epilepsy is a chronic disease that causes substantial morbidity and mortality. Pharmacists represent an integral role in managing patients with epilepsy. The aim of this study was to evaluate the level of knowledge about the pharmacology and pathophysiology of epilepsy among senior pharmacy students. Materials and Methods: Cross-sectional study using a designed questionnaire to measure the pharmacological and physiological knowledge of senior pharmacy students regarding epilepsy who are studying at Umm Al-Qura University, Makkah, Saudi Arabia, from August to October 2022. Results: A total of 211 senior clinical pharmacy students responded to the questionnaire. The majority of the respondents were 4th year pharmacy students. The numbers of female and male participants were equal (106 and 105 students, respectively). The participants represented an acceptable level of knowledge about the pathophysiology aspects of epilepsy, with a mean total score of 6.22 ± 1.9 out of a maximum score of 10. The respondents reported that epilepsy could be due to genetic predisposition combined with environmental conditions (80.1%) or brain stroke (17.1%). Regarding the respondent knowledge about the pharmacology of epilepsy, the total score was 4.6 ± 2.1 (maximum attainable score: 9). Conclusions: The majority of pharmacy students had knowledge about the pathophysiology concept of the disease; however, low knowledge was shown by the respondents regarding the pharmacology of epilepsy. Thus, there is a need to identify better strategies to improve students' education.

Development and validation of a simple method for the determination of triamcinolone acetonide in nasal spray.

A rapid, convenient, and sensitive analytical technique for quantitative analysis of triamcinolone acetonide (TAC) in pharmaceutical nasal spray dosage form using the blue tetrazolium colorimetric reaction and UV spectrophotometric method was developed and validated. Beer's law of the developed method was proven in the concentration range of 10-40 µg/mL and showed a specific linear relationship with coefficient value R2 = 0.998. The LOQ level was 9.99 µg/mL, with (RSD = 0.26%). From precision assay, RSD values have been obtained for the repeatability and intermediate precision, which were found to be (RSD = 1.65%) and (RSD = 2.01%), respectively, indicating that the method is reproducible. Recovery studies showed mean recoveries in the range of (100.08-103.65 %), meeting the acceptance criteria for accuracy. In addition, we compared the results of the developed method UV-Vis spectrophotometric procedure with those of a well-established official USP analytical procedure (HPLC), and the results showed good agreement. The proposed UV method represents a potential alternative to the official USP analytical assay procedure (HPLC) for estimating TAC in nasal spray forms. Furthermore, it has the potential to be implemented in routine use for rapid qualitative and quantitative determinations for TAC.

The complex regional pain syndrome: Diagnosis and management strategies.

Complex regional pain syndrome (CRPS) is a chronic disease that affects a limb following an injury or trauma. The CRPS associated with symptoms, including severe pain, swelling, as well as changes in skin color and temperature. Treatment of CRPS requires a multidisciplinary approach, with a focus on personalized treatment plans and addressing psychological factors. This review provides an overview of updates in the diagnosis and treatment of CRPS. There are clinical criteria for diagnosing CRPS, including persistent pain and swelling. The CRPS can also be diagnosed with imaging and laboratory tests. Novel insights into treatment approaches for CRPS have been gained from advances in understanding its pathophysiology. Treatment of CRPS includes both pharmacological and non-pharmacological interventions. The latest guidelines for CRPS treatment emphasize the importance of early diagnosis and intervention, personalized treatment plans, and addressing psychological factors in managing CRPS.

Cutaneous adverse reactions to coronavirus vaccines: A Saudi nationwide study.

The coronavirus vaccine was developed to help overcome the COVID-19 crisis. This study aimed to identify the cutaneous side effects secondary to Pfizer-BioNTech and Oxford-AstraZeneca COVID-19 vaccines in the general population of Saudi Arabia and to list the risk factors for the development of cutaneous side effects. This cross-sectional study was conducted in 2021, self-administered surveys were distributed electronically through social media, and telephonic interviews were conducted with a sample size of 1000 participants. Data analysis was performed using Statistical Package for the Social Sciences. A total of 1021 patients (229 male and 722 female) aged 12 years or older were included. While 833 participants were medically free, 188 had chronic illnesses. While 802 participants were not taking any medications, 219 were taking medications regularly. Oxford-Astra Zeneca and Pfizer BioNTech vaccines were administered to 319 and 702 participants, respectively. One-hundred and twenty-five participants previously had COVID-19 infection and 407 were exposed to a PCR positive case of COVID. Six hundred and fifty-nine patients (64.5%) reported experiencing injection site reactions: 606 (59.4%) had injection site pain, 168 (16.5%) had injection site swelling, and 107 (10.5%) had injection site redness. Only 51 patients (5%) experienced cutaneous side effects after injection. A significant association was found between chronic illnesses and cutaneous side effects post-vaccine (9% vs. 4.1%; p value = 0.005). Patients on medications showed a higher rate of symptoms (8.2% vs. 4.1%; p value = 0.005). Age, gender, vaccine types, and history of COVID-19 infection were not significantly associated with cutaneous side effects post-vaccine.

In vivo evidence of lumbricals incursion into the carpal tunnel in healthy hands: An ultrasonographic cross sectional study.

INTRODUCTION: During finger flexion, the tendons of flexor digitorum profundus migrate proximally, along with their attached lumbrical muscles. This incursion was suggested to extend into the Carpal Tunnel. Ultrasonographic imaging can be used to assess in vivo soft tissue behavior and incursion. PURPOSE OF THE STUDY: To clinically quantify the lumbrical muscles incursion in different finger positions. STUDY DESIGN: Cross sectional, observational study. METHODS: The lumbricals of 20 healthy adults with no history of hand injuries were evaluated with neuromuscular ultrasound imaging (n = 160 lumbricals). The lumbrical muscles migration was measured as the participants actively moved their fingers from full extension to 50% flexion, and 100% flexion. RESULTS: Of the 160 lumbricals measures, the incursion occurred at 18.1% of fingers at 50% finger flexion, and increased to 79.4% during full finger flexion. The lumbricals migrated a total of 2.99 cm after full finger flexion, and ended up 0.76 cm (SD = 0.86 cm) inside the Carpal Tunnel. The metacarpophalangeal joint range of motion of the index finger at the point where the lumbricals entered the distal border of the Transverse Carpal Ligament was 84.4° (SD = 6.8°). The Carpal Tunnel cross-sectional area during finger extension was 1.68 (0.35) cm2, and increased to 1.81 (0.33) cm2 after full finger flexion. CONCLUSION: This study showed direct evidence of lumbrical incursion into the Carpal Tunnel during finger flexion. The cross-sectional area of the Carpal Tunnel increased during full finger flexion in comparison to full finger extension, supplementing the evidence of increase content within the Carpal Tunnel. The findings of this study have significant clinical implications for the conservative treatment of the Capral Tunnel Syndrome.

Efficacy and safety of delafloxacin, ceftaroline, ceftobiprole, and tigecycline for the empiric treatment of acute bacterial skin and skin structure infections: A network meta-analysis of randomized controlled trials.

Background: This review aimed to conduct an indirect comparison using a Bayesian network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of delafloxacin versus other single antibiotic regimens for the empiric treatment of Acute Bacterial Skin and Skin Structure Infections. Method: A systematic search with no start date restrictions was conducted. The Cochrane Risk of Bias tool was used to assess the quality of included RCTs. Results: Of the 577 studies initially identified, nine RCTs were included in the review. The network meta-analysis showed that ceftaroline, ceftobiprole, delafloxacin and tigecycline had similar efficacy in the indirect comparisons [Ceftaroline Odds Ratio (OR) = 1.2, 95% Crl = 0.46-3.6), ceftobiprole (OR = 1.3, 95% Crl = 0.34-3.0) and tigecycline (OR = 0.96, 95% Crl = 0.30-2.9)]. However, the ranking plot for the intention to treat (ITT) population showed that delafloxacin had a probability of 80.8% to be ranked first followed by ceftobiprole (13.1%). The analysis of the overall adverse events showed that ceftaroline (OR = 0.88, 95% Crl = 0.65-1.2), ceftobiprole (OR = 1.1, 95% Crl = 0.69-2.0), delafloxacin (OR = 0.88, 95% Crl = 0.57-1.3) and tigecycline (OR = 1.4, 95% Crl = 0.88-2.2) had similar safety profiles. Conclusion: Delafloxacin did not show any statistically significant differences when compared to ceftaroline, ceftobiprole, and tigecycline in terms of efficacy and safety. However, the surface under the cumulative ranking curve (SUCRA) probability ranked delafloxacin as the first option for the ITT population.

Thrombus Migration and Fragmentation After Intravenous Alteplase Treatment: The INTERRSeCT Study.

BACKGROUND AND PURPOSE: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. METHODS: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0-3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. RESULTS: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2-3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0-1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0-2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72-20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21-5.51]). CONCLUSIONS: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.

Spheno-orbital juvenile psammomatoid ossifying fibroma: a case report and literature review.

Ossifying fibroma (OF) is an uncommon benign fibro-osseous lesion. Based on its clinical, morphological, and radiological features, OF is further divided into cemento-ossifying fibroma (COF), juvenile psammomatoid ossifying fibroma (JPOF), and juvenile trabecular ossifying fibroma (JTOF). JPOF rarely involves the cranial base, with limited reports published on spheno-orbital JPOF. In this paper, we report a case of JPOF of the greater wing of the sphenoid bone and lateral orbital wall in an 11-year-old child and show a surgical video. Although rare, JPOF should be considered in the differential diagnosis of fibro-osseous lesions of the spheno-orbital region.

Bibliometric analysis of the top 100 most cited articles on craniosynostosis.

BACKGROUND: Craniosynostosis is the premature closure of cranial sutures and it continues to be a therapeutic challenge due to the diversity and complexity of the syndrome. Bibliometric analysis is a study of ranking citations and exploring the most impactful articles in a respective discipline. It also demonstrates the chronological trends of publications. METHODS: In May 2020, we performed a title-specific search of the Scopus database using "craniosynostosis" as our query term without publication date restrictions. The top 100 articles in craniosynostosis were retrieved and analyzed. RESULTS: The top 100 most-cited articles in craniosynostosis received a total 13,826 citations, and an average of 138 citations per paper. The publication dates ranged from 1920 to 2015, with a peak period of top publications between 1996 and 2005. The most common category is clinical, followed by neurogenetics. The top cited article received 540 citation counts and 19.29 citations per year. The USA was the most contributing country to the list. The Journal of Plastic and Reconstructive Surgery published the largest number of top cited articles. Neurosurgery as a specialty contributed to most articles in the list (27 articles). The institute who contributed the most was the Assistance Publique Hopitaux Paris. CONCLUSION: Bibliometric analysis in craniosynostosis revealed major trend changes of research over the years, with a focus on neurogenetics and the different types of surgical corrections. The current collection of highly cited publications may assist physicians in gaining a better understanding of the evidence-based approach in craniosynostosis.

Factor XIII-A: An Indispensable "Factor" in Haemostasis and Wound Healing.

Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA2B2, has an established function in haemostasis, with fibrin being its principal substrate. A deficiency in FXIII manifests as a severe bleeding diathesis emphasising its crucial role in this pathway. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage. The cellular form, a homodimer of the A subunits denoted FXIII-A, was perceived to remain intracellular, due to the lack of a classical signal peptide for its release. It is now apparent that FXIII-A can be externalised from cells, by an as yet unknown mechanism. Thus, three pools of FXIII-A exist within the circulation: plasma where it circulates in complex with the inhibitory FXIII-B subunits, and the cellular form encased within platelets and monocytes/macrophages. The abundance of this transglutaminase in different forms and locations in the vasculature reflect the complex and crucial roles of this enzyme in physiological processes. Herein, we examine the significance of these pools of FXIII-A in different settings and the evidence to date to support their function in haemostasis and wound healing.

Monocytes Expose Factor XIII-A and Stabilize Thrombi against Fibrinolytic Degradation.

Factor XIII (FXIII) is a transglutaminase that promotes thrombus stability by cross-linking fibrin. The cellular form, a homodimer of the A subunits, denoted FXIII-A, lacks a classical signal peptide for its release; however, we have shown that it is exposed on activated platelets. Here we addressed whether monocytes expose intracellular FXIII-A in response to stimuli. Using flow cytometry, we demonstrate that FXIII-A antigen and activity are up-regulated on human monocytes in response to stimulation by IL-4 and IL-10. Higher basal levels of the FXIII-A antigen were noted on the membrane of the monocytic cell line THP-1, but activity was significantly enhanced following stimulation with IL-4 and IL-10. In contrast, treatment with lipopolysaccharide did not upregulate exposure of FXIII-A in THP-1 cells. Quantification of the FXIII-A activity revealed a significant increase in THP-1 cells in total cell lysates following stimulation with IL-4 and IL-10. Following fractionation, the largest pool of FXIII-A was membrane associated. Monocytes were actively incorporated into the fibrin mesh of model thrombi. We found that stimulation of monocytes and THP-1 cells with IL-4 and IL-10 stabilized FXIII-depleted thrombi against fibrinolytic degradation, via a transglutaminase-dependent mechanism. Our data suggest that monocyte-derived FXIII-A externalized in response to stimuli participates in thrombus stabilization.

Pro-Inflammatory and Neurotrophic Factor Responses of Cells Derived from Degenerative Human Intervertebral Discs to the Opportunistic Pathogen Cutibacterium acnes.

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1ß, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1ß, and other known IL-1ß-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1ß, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1ß and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection.