Reference Values of Ceruloplasmin across the Adult Age Range in a Large Italian Healthy Population.

BACKGROUND: Ceruloplasmin (Cp) is the most important serum copper transport protein playing a key role in the binding of iron to transferrin. It is a positive acute-phase response protein and the first-level diagnostic marker for Wilson disease and aceruloplasminemia. However, standardization of Cp measurement has not been successful, and assay specific reference levels of Cp are required. METHODS: From May 2019 to July 2022, we enrolled 1706 consecutive healthy Italian blood donors (1285 men and 421 women, 18 to 65 years) to identify the reference intervals of serum Cp through quantile regression and evaluate the relationship of Cp with age, sex, iron, and metabolic status through linear regression. RESULTS: We found that mean serum Cp was influenced by sex and slightly by age. The lower reference Cp value rose slightly with increasing age in both men and women. The upper reference value increased, reaching a plateau of about 25 mg/dL around 25 years in men, while in women it initially increased to around 45 mg/dL in young adults to fall sharply below 30 mg/dL for adults after their fifties. CONCLUSIONS: We showed that the normal reference curves of serum Cp vary according to sex in a large population of healthy adults. While the lower reference values did not appear to be influenced by age and sex, the upper ones differed according to sex and age showing a particularly high variability in women, possibly reflecting different hormonal status.

Fibroblast and myofibroblast activation in normal tissue repair and fibrosis.

The term 'fibroblast' often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast-myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.

Rebuilding and rebooting immunity with stem cells.

Advances in modern medicine have enabled a rapid increase in lifespan and, consequently, have highlighted the immune system as a key driver of age-related disease. Immune regeneration therapies present exciting strategies to address age-related diseases by rebooting the host's primary lymphoid tissues or rebuilding the immune system directly via biomaterials or artificial tissue. Here, we identify important, unanswered questions regarding the safety and feasibility of these therapies. Further, we identify key design parameters that should be primary considerations guiding technology design, including timing of application, interaction with the host immune system, and functional characterization of the target patient population.

Origins and functions of eosinophils in two non-mucosal tissues.

Eosinophils are a type of granulocyte named after the presence of their eosin-stained granules. Traditionally, eosinophils have been best known to play prominent roles in anti-parasitic responses and mediating allergic reactions. Knowledge of their behaviour has expanded with time, and they are now recognized to play integral parts in the homeostasis of gastrointestinal, respiratory, skeletal muscle, adipose, and connective tissue systems. As such, they are implicated in a myriad of pathologies, and have been the target of several medical therapies. This review focuses on the lifespan of eosinophils, from their origins in the bone marrow, to their tissue-resident role. In particular, we wish to highlight the functions of eosinophils in non-mucosal tissues with skeletal muscle and the adipose tissues as examples, and to discuss the current understanding of their participation in diseased states in these tissues.

The paradigm shift in treatment of severe venous thromboembolism.

Pulmonary embolism (PE) is the third leading cause of cardiovascular death and the main cause of preventable in-hospital death in the world. The PERT® (Pulmonary Embolism Response Team) concept involves multidisciplinary diagnosis and immediate treatment. Deep venous thrombosis (DVT) is the initial cause of most cases of PE and is responsible for complications such as chronic thromboembolic recurrence, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension. An aggressive approach to severe cases of iliofemoral DVT similar to the PERT® system can not only reduce the immediate risk of PE and death but can also reduce later sequelae. New percutaneous techniques and mechanical thrombectomy devices for venous thromboembolism (VTE) have shown encouraging clinical results. We propose the development of an expanded concept of rapid response to VTE, which involves not only PE (PERT®) but also severe cases of DVT: the Venous Thromboembolism Response Team (VTERT®).

Toward a person-centered ethics framework for autonomy in spinal cord injury research and rehabilitation.

In this paper, we explore how the concepts of autonomy and autonomous choice are understood in the context of spinal cord injury in the academic literature, both in reporting on research results and more broadly on outcomes and quality of life. We find inconsistent, framework-absent portrayals of autonomy as well as an absence of discourse that draws upon ethical constructs and theory. In response, we advance a person-centered framework for spinal cord injury research that combines both lived experience and a disability ethics approach to fill this gap.

Cellular activation patterns of CD10+ fibro-adipogenic progenitors across acquired disease states in human skeletal muscle biopsies.

Background: Fibro-adipogenic progenitors (FAP) are muscle resident mesenchymal stem cells pivotal for regulation of myofiber repair. Experimental results show in addition involvement in a range of other pathological conditions and potential for pharmacological intervention. FAP histopathology in human muscle biopsies is largely unknown, but has potential to inform translational research. Methods: CD10+ FAPs in 32 archival muscle biopsies from 8 groups (normal, dermatomyositis, inclusion body myositis (IBM), anti-synthetase syndrome, immune-mediated necrotizing myopathy (IMNM), denervation, type 2 atrophy, rhabdomyolysis) were visualized by CD10 immunohistochemistry and their histology compared. Groups are compared by semi-quantitative scoring. Results: Histological activation of endomysial CD10+ FAPs includes prominent expansion of a network of cell processes surrounding muscle fibers, as well as endomysial cell clusters evidencing proliferation. Prominence of periarteriolar processes is a notable feature in some pathologies. FAP activation is often associated with fiber degeneration/regeneration, foci of inflammation, and denervation in keeping with experimental results. Type 2 atrophy shows no evidence of FAP activation. Dermatomyositis and anti-synthetase syndrome associated myositis demonstrate diffuse activation. Conclusion: Assessment of CD10+ FAP activation is routinely possible using CD10 immunohistochemistry and demonstrates several patterns in keeping with preclinical results. Prominent expansion of FAP processes surrounding myofibers suggests enhanced interaction between myofiber/basement membranes and FAPs during activation. The presence of diffuse FAP activation in dermatomyositis biopsies unrelated to fiber repair raises the possibility of FAP activation as part of the autoimmune process. Future diagnostic applications, clinical significance and therapeutic potential remain to be elucidated.

Diagnosis of chronic iliac venous obstruction.

Stenting has become the first line of treatment for symptomatic chronic iliofemoral venous obstruction in patients with quality-of-life-impairing clinical manifestations who have failed conservative therapy. Patient selection for such intervention is, however, dependent on clear identification of relevant clinical manifestations and subsequent testing to confirm the diagnosis. In this regard, the physician engaged in management of such patients needs to be well-aware of symptoms and signs of chronic iliofemoral venous obstruction, and instruments used to grade chronic venous insufficiency and determine quality of life, in addition to diagnostic tests available and their individual roles. This review serves to provide an overview of the diagnosis of chronic iliofemoral venous obstruction and patient selection for stenting.

Diagnosis of chronic iliac venous obstruction

Stenting has become the first line of treatment for symptomatic chronic iliofemoral venous obstruction in patients with quality-of-life impairing clinical manifestations who have failed conservative therapy. Patient selection for such intervention is however dependant on clear identification of relevant clinical manifestations and subsequent testing to confirm the diagnosis. In this regard the physician engaged in management of such patients need to be well aware of symptoms and signs of chronic iliofemoral venous obstruction (CIVO), instruments used to grade chronic venous insufficiency (CVI) and determine quality of life in addition to diagnostic tests available and their individual roles. This review serves to provide an overview of the diagnosis of CIVO and patient selection for stenting.

A mudança de paradigma no tratamento do tromboembolismo venoso grave / The paradigm shift in treatment of severe venous thromboembolism

Resumo A embolia pulmonar (EP) é a terceira maior causa de morte cardiovascular e a principal de morte evitável intra-hospitalar no mundo. O conceito PERT® (do inglês, pulmonary embolism response team) envolve seu diagnóstico e tratamento precoce e multidisciplinar. A trombose venosa profunda (TVP) é a sua causa inicial na maioria dos casos e é responsável por complicações como a recidiva tromboembólica, a síndrome pós-trombótica e a hipertensão pulmonar tromboembólica crônica. Uma abordagem inicial semelhante ao PERT nos casos de TVP ilíaco-femoral grave pode reduzir não apenas o risco imediato de EP e morte, mas também suas sequelas tardias. Novas técnicas percutâneas e aparatos de trombectomia mecânica para o tromboembolismo venoso (TEV) vêm demonstrando resultados clínicos encorajadores. Propomos o desenvolvimento de um conceito ampliado de resposta rápida ao TEV, que envolve não apenas a EP (PERT®) mas também os casos graves de TVP: o time de resposta rápida para o TEV (TRETEV®), ou do inglês Venous Thromboembolism Response Team (VTERT®).

Abstract Pulmonary embolism (PE) is the third leading cause of cardiovascular death and the main cause of preventable in-hospital death in the world. The PERT® (Pulmonary Embolism Response Team) concept involves multidisciplinary diagnosis and immediate treatment. Deep venous thrombosis (DVT) is the initial cause of most cases of PE and is responsible for complications such as chronic thromboembolic recurrence, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension. An aggressive approach to severe cases of iliofemoral DVT similar to the PERT® system can not only reduce the immediate risk of PE and death but can also reduce later sequelae. New percutaneous techniques and mechanical thrombectomy devices for venous thromboembolism (VTE) have shown encouraging clinical results. We propose the development of an expanded concept of rapid response to VTE, which involves not only PE (PERT®) but also severe cases of DVT: the Venous Thromboembolism Response Team (VTERT®).

DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.

Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. While the presence of a nurturing niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice (PdgfrαCreERT2 × DTA) or mice lacking FAP-derived CSF1 (PdgfrαCreERT2 × Csf1flox/null), we show that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4+ RMs coincide with those of dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.

Spatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction.

Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac stroma, specifically mural cells, and their response to ischemic injury. Here, we combine single-cell and positional transcriptomics to assess the behavior of mural cells within the healing heart. In response to myocardial infarction, mural cells adopt an altered state closely associated with the infarct and retain a distinct lineage from fibroblasts. This response is concurrent with vascular rarefaction and reduced vascular coverage by mural cells. Positional transcriptomics reveals that the infarcted heart is governed by regional-dependent and temporally regulated programs. While the remote zone acts as an important source of pro-angiogenic signals, the infarct zone is accentuated by chronic activation of anti-angiogenic, pro-fibrotic, and inflammatory cues. Together, our work unveils the spatiotemporal programs underlying cardiac repair and establishes an association between vascular deterioration and mural cell dysfunction.

Management of traumatic superficial palmar arch pseudoaneurysm: a therapeutic challenge.

Pseudoaneurysm of the palmar arch is a rare entity. Diagnosis is dependent on high clinical suspicion. We present a case referred to the emergency department, with a history of glass penetrating trauma to the palmar surface with a pulsatile mass and jet bleeding. Doppler ultrasound evidenced a partially thrombosed pseudoaneurysm. A CT angiography examination showed a saccular formation arising from the superficial palmar arch. A conventional surgical approach was indicated. A clinical suspicion must be ventured to arrive at the correct diagnosis. Imaging modalities are needed to identify the pseudoaneurysm and plan the treatment course. Nonetheless, the sequence of diagnosis is individual, because further evaluation with different imaging methods may not change the rationale for the intervention. In our experience, conventional surgical removal is preferable, due to its safety and well-established outcomes.

O pseudoaneurisma do arco palmar é uma entidade rara, cujo diagnóstico depende de alta suspeição clínica. Apresentamos o caso de um paciente encaminhado ao pronto-socorro com história de traumatismo penetrante por vidro na face palmar, com massa pulsátil e sangramento em jato. A ultrassonografia com Doppler evidenciou pseudoaneurisma parcialmente trombosado, e a angiotomografia demonstrou formação sacular originada do arco palmar superficial. Uma abordagem cirúrgica convencional foi indicada. Para prosseguir com o diagnóstico correto, essa suspeita clínica deve ser aventada. Modalidades de imagem são necessárias para identificar o pseudoaneurisma e planejar o curso do tratamento. No entanto, a sequência diagnóstica é individual, pois uma avaliação mais aprofundada, com diferentes métodos de imagem, pode não alterar o racional da intervenção. Em nossa experiência, a remoção cirúrgica convencional é preferível, visto sua segurança e seus resultados bem estabelecidos.

Protocol for generation of a time-resolved cellular interactome during tissue remodeling in adult mice.

Efficient skeletal muscle regeneration necessitates fine-tuned coordination among multiple cell types through an intricate network of intercellular communication. We present a protocol for generation of a time-resolved cellular interactome during tissue remodeling. We describe steps for isolating distinct cell populations from skeletal muscle of adult mice after acute damage and extracting RNA from purified cells prior to the generation of RNA sequencing data. We then detail procedures for generating and deciphering a time- and lineage-resolved model of intercellular crosstalk. For complete details on the use and execution of this protocol, please refer to Groppa et al. (2023).1.

Aneurisma da artéria dorsal do pé: relato de caso: resumo / Aneurysm of the dorsal artery of the foot: case report modality: abstract

RESUMO: Paciente do sexo feminino, 59 anos, comerciante. Assintomática até há 1 ano, quando observou surgimento de massa pulsátil em dorso do pé direito, eventualmente dolorosa.

Efficacy and safety of iliofemoral bypass using arm veins as an alternative conduit for chronic limb-threatening ischemia.

OBJECTIVE: The use of basilic vein in iliofemoral revascularizations was previously described in the literature as an autologous option for the treatment of vascular prosthesis infection and as a primary conduit in patients at high risk of infectious surgical complications. However, the publications available include several different indications and are limited to case reports. Therefore, the aim of this study was to evaluate the outcomes of the use of arm veins as a safe and effective autologous alternative for iliofemoral reconstruction in patients with chronic limb-threatening ischemia (CLTI) and at high risk of prosthesis infection. METHODS: We performed a multicenter, retrospective cohort study with 53 consecutive iliofemoral bypasses using arm veins as an alternative conduit. The procedures were performed between November 2013 and November 2021, exclusively for patients with CLTI classified as TASC aortoiliac C or D with increased risk of postoperative surgical infection. Demographic, clinical variables, and outcomes were collected from a prospective database. Main endpoints were amputation-free survival (AFS) and major adverse cardiovascular events. Secondary endpoints included primary and secondary patencies and overall survival. Cox regression analysis was used to identify the predictors of AFS. Postoperative surgical complications and 30-day mortality were also assessed. RESULTS: The mean age was 64.2 ± 8.4 years, with a predominance of male gender. The median follow-up period was 615 days. All patients had CLTI, with a predominance of tissue loss (n = 51; 96.2%) and a median ankle-brachial index of 0.28. The basilic vein was utilized in most procedures (69.8%). Thirty-day major adverse cardiovascular events occurred in five cases (9.4%), and the 30-day mortality rate was 3.8%. The AFS, primary patency, secondary patency, and overall survival in 720 days were 71%, 72%, 89%, and 75%, respectively. Cox regression analysis revealed no association between the variables analyzed for AFS. There was no graft late infection nor pseudoaneurysmal degeneration. CONCLUSIONS: Iliofemoral bypass using arm veins as an autologous conduit proved to be an effective and safe procedure with low incidence of postoperative cardiovascular complications and high rates of AFS in patients with CLTI. Also, this suggests that arm veins can be an interesting and suitable autologous alternative conduit for iliofemoral reconstructions, especially in cases in which a prosthesis should be avoided or when it is not available.

Association between the degree of iliac venous outflow obstruction by intravascular ultrasound and lower limb venous reflux.

OBJECTIVE: The present study aims to evaluate the association between the degree of iliac venous outflow obstruction (IVOO) identified by intravascular ultrasound (IVUS) and venous reflux presentation in the lower limbs on duplex ultrasound (DU). METHODS: Patients with bilateral chronic venous insufficiency, CEAP (clinical-etiology-anatomy-pathophysiology) C3 to C6, and a visual analog scale score for pain >5 underwent DU for reflux evaluation of the deep venous system (reflux ≥1 second); superficial system, great saphenous vein, and small saphenous vein (reflux ≥0.5 second); and perforator system (reflux ≥0.35 second). All patients underwent IVUS in the iliac venous territory. The area of the impaired venous segments was categorized as obstruction <50% (category 1), 50% to 79% (category 2), and ≥80% (category 3). The venous clinical severity score and reflux multisegment score (RMS) were assessed. RESULTS: A total of 51 patients (n = 102 limbs; age, 50.53 ± 14.5 years; 6 men) were included. The predominant clinical severity CEAP class was C3 in 54 of 102 limbs (52.9%). The mean VCSS was 14.3 ± 6.7. A severe RMS (≥3) was registered in 63.4% of the limbs. Of the 102 limbs, 51 (50%) presented with category 1, 27 (26.5%) with category 2, and 24 (23.5%) with category 3. Previous deep vein thrombosis (DVT) was associated with critical obstruction (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.29-10.38; P = .015). The superficial and perforator venous systems had no association with the degree of IVOO. Deep venous reflux (DVR) had a significant association with significant IVOO (obstruction ≥50%; OR, 6.44; 95% CI, 2.19-18.93; P = .001) and critical IVOO (obstruction ≥80%; OR, 4.57; 95% CI, 1.70-12.27; P = .003) and a significant linear association with the IVOO degree and reflux in the femoral veins (P < .001) and popliteal vein (P = .008). Significant lesions were significantly more likely to develop in the left limb (OR, 5.76; 95% CI, 2.46-13.50; P < .001). After multivariate analysis, DVR remained a predictor for significant and critical obstruction (P < .003 and P < .012, respectively). Left limb and previous DVT remained as predictors for IVOO of ≥50% and ≥80% (P < .001 and P = .043, respectively). CONCLUSIONS: We found a significant linear association between the degree of IVOO and reflux in the deep venous system on DU. Limbs with DVR, a severe RMS, loss of respiratory variation on DU, and previous DVT were more likely to be affected by IVOO of ≥50%, especially with left leg involvement.

Association between the degree of iliac venous outflow obstruction by intravascular ultrasound and lower limbs venous reflux

OBJECTIVE: This study aims to evaluate the association between the degree of iliac venous outflow obstruction (IVOO) identified by Intravascular Ultrasound (IVUS) and venous reflux presentation in lower limbs on Duplex Ultrasound (DU). METHODS: Patients with bilateral chronic venous insufficiency, CEAP C3-6 (Clinical-Etiology-Anatomy-Pathophysiology classification), and with Visual Analogic Scale score for pain > 5, underwent DU for reflux evaluation: deep venous system (reflux ≥ 1 s); superficial system, great saphenous vein (GSV) and small saphenous vein (SSV) (reflux ≥ 0.5 s); perforator system (reflux ≥ 0.35s). All patients underwent IVUS in the iliac venous territory. The area of the impaired venous segments was categorized as obstructions< 50% (Cat. 1); 50-79% (Cat. 2), and ≥ 80% (Cat. 3). Venous clinical severity scale (VCSS) and reflux multisegment score (RMS) were assessed. RESULTS: 51 patients (n=102 limbs; 50.53 ± 14.5 years, 6 men) were included. The predominant clinical severity CEAP class was C3 in 54/102 (52.9%) limbs. VCSS mean was 14.3 ± 6.7. Severe RMS (≥ 3) was registered in 63,4% of the limbs. In 51/102 limbs (50%) presented cat. 1, 27/102 (26.5%) cat. 2, and 24/102 (23.5%) cat. 3. Previous DVT was associated with critical obstruction (OR 3.65; 95% CI: 1.29-10.38; p=0.015). Superficial and perforator venous systems had no association with the degree of iliac obstruction. Deep venous reflux (DVR) had a significant association with significative IVOO (obstruction ≥ 50%) (OR 6.44; 95% CI: 2.19-18.93; p=0.001) and critical IVOO (obstruction ≥ 80%) (OR 4.57; 95% CI: 1.70-12.27; p=0.003), and significant linear association with IVOO degree and reflux in femoral veins (p<0.001) and popliteal vein (p=0.008). Significant lesions had 5.76 (95% CI: 2.46-13.50; p<0.001) more odds of happening in the left limb. After a multivariate analysis, DVR remained as predictor for significant and critical obstruction (p<0.003, p< 0.012; respectively). Left limb and previous DVT remained as predictors for IVOO ≥50% and IVOO≥ 80% (p<0.001, p=0.043; respectively) CONCLUSIONS: There is a significant linear association between the degree of iliac venous outflow obstruction and reflux in the deep venous system on DU. Limbs with DVR, severe RMS, loss of respiratory variation on DU, and previous DVT, were more likely to be affected by IVOO ≥ 50%, especially with the left leg involvement.

Efficacy and safety of iliofemoral bypass using arm veins as an alternative conduit for chronic limb-threatening ischemia

OBJECTIVE: The use of basilic vein in iliofemoral revascularizations was previously described in the literature as an autologous option for the treatment of vascular prosthesis infection and as a primary conduit in patients at high risk of infectious surgical complications. However, the publications available include several different indications and are limited to case reports. Therefore, the aim of this study was to evaluate the outcomes of the use of arm veins as a safe and effective autologous alternative for iliofemoral reconstruction in patients with chronic limb-threatening ischemia (CLTI) and at high risk of prosthesis infection. METHODS: We performed a multicenter, retrospective cohort study with 53 consecutive iliofemoral bypasses using arm veins as an alternative conduit. The procedures were performed between November 2013 and November 2021, exclusively for patients with CLTI classified as TASC aortoiliac C or D with increased risk of postoperative surgical infection. Demographic, clinical variables, and outcomes were collected from a prospective database. Main endpoints were amputation-free survival (AFS) and major adverse cardiovascular events. Secondary endpoints included primary and secondary patencies and overall survival. Cox regression analysis was used to identify the predictors of AFS. Postoperative surgical complications and 30-day mortality were also assessed. RESULTS: The mean age was 64.2 ± 8.4 years, with a predominance of male gender. The median follow-up period was 615 days. All patients had CLTI, with a predominance of tissue loss (n = 51; 96.2%) and a median ankle-brachial index of 0.28. The basilic vein was utilized in most procedures (69.8%). Thirty-day major adverse cardiovascular events occurred in five cases (9.4%), and the 30-day mortality rate was 3.8%. The AFS, primary patency, secondary patency, and overall survival in 720 days were 71%, 72%, 89%, and 75%, respectively. Cox regression analysis revealed no association between the variables analyzed for AFS. There was no graft late infection nor pseudoaneurysmal degeneration. CONCLUSIONS: Iliofemoral bypass using arm veins as an autologous conduit proved to be an effective and safe procedure with low incidence of postoperative cardiovascular complications and high rates of AFS in patients with CLTI. Also, this suggests that arm veins can be an interesting and suitable autologous alternative conduit for iliofemoral reconstructions, especially in cases in which a prosthesis should be avoided or when it is not available.