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1.
Vasc Endovascular Surg ; 56(1): 95-97, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34474621

RESUMO

Case presentation: We present a case of a patient with a syphilitic popliteal pseudoaneurysm who developed acute lower-limb ischemia secondary to thromboembolism related to the pseudoaneurysm. The diagnosis of a syphilitic popliteal aneurysm was made due to positive syphilitic serological testing and with exclusion of all other potential causes. The pseudoaneurysm was surgically repaired using a great saphenous vein patch angioplasty, which was done without delay to prevent further thromboembolic complications. This was then followed by a course of intravenous benzyl penicillin. Discussion: Peripheral arterial involvement of tertiary syphilis remains exceedingly rare, with the vast majority of reported cases of vascular syphilis relating to aortic involvement. Given the paucity of literature on this condition, there is no good evidence to guide current management. Conclusion: With the globally increasing rates of syphilis, more cases of peripheral arterial involvement may become apparent, as was the case in the early 20th century.


Assuntos
Falso Aneurisma , Aneurisma , Falso Aneurisma/diagnóstico por imagem , Falso Aneurisma/etiologia , Falso Aneurisma/cirurgia , Humanos , Isquemia/diagnóstico por imagem , Isquemia/etiologia , Isquemia/terapia , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/cirurgia , Resultado do Tratamento
2.
Emerg Med Clin North Am ; 39(4): 769-780, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34600636

RESUMO

Abdominal vascular emergencies are an uncommon entity in emergency medicine, but when they present, they are often catastrophic. These time-sensitive and life-threatening diagnoses are often hidden in nonspecific complaints such as nausea, vomiting, or flank pain, so the emergency physician must remain diligent and consider these in the differential diagnoses. The following is an overview of the more common of these abdominal vascular emergencies, in the hope that they help the Emergency Physician avoid the misdiagnosis and subsequent vascular catastrophe that would follow.


Assuntos
Abdome/irrigação sanguínea , Erros de Diagnóstico/prevenção & controle , Traumatismos Abdominais/diagnóstico , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/cirurgia , Estenose da Valva Aórtica/diagnóstico , Arteriopatias Oclusivas/diagnóstico , Técnicas de Diagnóstico do Sistema Digestório , Medicina de Emergência , Humanos , Intestinos/irrigação sanguínea , Isquemia/diagnóstico , Isquemia/terapia , Isquemia Mesentérica/diagnóstico , Isquemia Mesentérica/terapia , Lesões do Sistema Vascular/diagnóstico
3.
Circ Cardiovasc Interv ; 14(11): e010635, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34706553

RESUMO

BACKGROUND: There are limited data on differences in angiographic distribution of peripheral artery disease and endovascular revascularization strategies in patients presenting with intermittent claudication (IC) and critical limb ischemia (CLI). We aimed to compare anatomic features, treatment strategies, and clinical outcomes between patients with IC and CLI undergoing endovascular revascularization. METHODS: We examined 3326 patients enrolled in the Excellence in Peripheral Artery Disease registry from 2006 to 2019 who were referred for endovascular intervention for IC (n=1983) or CLI (n=1343). The primary outcome was 1-year major adverse limb events, which included death, repeat target limb revascularization, or target limb amputation. RESULTS: Patients with CLI were older and more likely to have diabetes and chronic kidney disease and less likely to receive optimal medical therapy compared with IC. Patients with IC had higher femoropopliteal artery interventions (IC 87% versus CLI 65%; P<0.001), while below the knee interventions were more frequent in CLI (CLI 47% versus IC 12%; P<0.001). Patients with CLI were more likely to have multilevel peripheral artery disease (CLI 32% versus IC 15%, P<0.001). Patients with IC were predominantly revascularized with stents (IC 48% versus CLI 37%; P<0.001) while balloon angioplasty was more frequent in CLI (CLI 37% versus IC 25%; P<0.001). All-cause mortality was higher in patients with CLI (CLI 4% versus IC 2%; P=0.014). Major adverse limb event rates for patients with IC and CLI were 16% and 26%, respectively (P<0.001) and remained higher in CLI after multivariable adjustment of baseline risk factors. CONCLUSIONS: Patients with IC and CLI have significant anatomic, lesion, and treatment differences with significantly higher mortality and adverse limb outcomes in CLI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01904851. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Procedimentos Endovasculares , Doença Arterial Periférica , Amputação , Procedimentos Endovasculares/efeitos adversos , Humanos , Claudicação Intermitente/diagnóstico por imagem , Claudicação Intermitente/epidemiologia , Isquemia/diagnóstico por imagem , Isquemia/terapia , Salvamento de Membro , Doença Arterial Periférica/cirurgia , Doença Arterial Periférica/terapia , Sistema de Registros , Fatores de Risco , Resultado do Tratamento
4.
Cardiol Clin ; 39(4): 483-494, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34686261

RESUMO

Chronic limb-threatening ischemia requires aggressive risk factor management and a thoughtful approach to the complex decision of best strategy for revascularization. Patients often have multilevel disease amenable to endovascular, open surgical, or hybrid approaches. Limited high-quality evidence is available to support a specific strategy; randomized trials are ongoing. Acute limb ischemia is associated with a high risk of limb loss and mortality. Catheter-directed thrombolysis is mainstay of therapy in patients with marginally threatened limbs, whereas those immediately threatened with motor deficits require more rapid restoration of flow with open or endovascular techniques that can establish flow in single setting.


Assuntos
Procedimentos Endovasculares , Doença Arterial Periférica , Amputação , Humanos , Isquemia/terapia , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/terapia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
5.
J Urol ; 206(5): 1114-1121, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34495686

RESUMO

PURPOSE: Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation and results in a prolonged and uncontrolled erection. Given its time-dependent and progressive nature, priapism is a situation that both urologists and emergency medicine practitioners must be familiar with and comfortable managing. Acute ischemic priapism, characterized by little or no cavernous blood flow and abnormal cavernous blood gases (ie, hypoxic, hypercarbic, acidotic) represents a medical emergency and may lead to cavernosal fibrosis and subsequent erectile dysfunction. MATERIALS AND METHODS: A comprehensive search of the literature was performed by Emergency Care Research Institute for articles published between January 1, 1960 and May 1, 2020. Searches identified 2948 potentially relevant articles, and 2516 of these were excluded at the title or abstract level for not meeting inclusion criteria for any key question. Full texts for the remaining 432 articles were reviewed, and ultimately 137 unique articles were included in the report. RESULTS: This Guideline was developed to inform clinicians on the proper diagnosis and surgical and non-surgical treatment of patients with acute ischemic priapism. This Guideline addresses the role of imaging, adjunctive laboratory testing, early involvement of urologists when presenting to the emergency room, discussion of conservative therapies, enhanced data for patient counseling on risks of erectile dysfunction and surgical complications, specific recommendations on intracavernosal phenylephrine with or without irrigation, the inclusion of novel surgical techniques (eg, tunneling), and early penile prosthesis placement. CONCLUSIONS: All patients with priapism should be evaluated emergently to identify the sub-type of priapism (acute ischemic versus non-ischemic) and those with an acute ischemic event should be provided early intervention. Treatment of the acute ischemic patient must be based on patient objectives, available resources, and clinician experience. As such, a single pathway for managing the condition is oversimplified and no longer appropriate. Using a diversified approach, some men may be treated with intracavernosal injections of phenylephrine alone, others with aspiration/irrigation or distal shunting, and some may undergo non-emergent placement of a penile prosthesis.


Assuntos
Tratamento de Emergência/normas , Disfunção Erétil/prevenção & controle , Isquemia/terapia , Priapismo/terapia , Urologia/normas , Doença Aguda/terapia , Adulto , Terapia Combinada/métodos , Terapia Combinada/normas , Tratamento de Emergência/métodos , Disfunção Erétil/etiologia , Disfunção Erétil/fisiopatologia , Humanos , Isquemia/etiologia , Isquemia/fisiopatologia , Masculino , América do Norte , Ereção Peniana/fisiologia , Pênis/diagnóstico por imagem , Pênis/efeitos dos fármacos , Pênis/fisiopatologia , Pênis/cirurgia , Fenilefrina/administração & dosagem , Priapismo/diagnóstico , Priapismo/etiologia , Priapismo/fisiopatologia , Sociedades Médicas/normas , Fatores de Tempo , Ultrassonografia Doppler , Urologia/métodos
6.
J Control Release ; 338: 773-783, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34530052

RESUMO

Pro-angiogenic growth factors have been studied as potential therapeutics for cardiovascular diseases like critical limb ischemia (CLI). However, the translation of these factors has remained a challenge, in part, due to problems associated with safe and effective delivery. Here, we describe a hydrogel-based delivery system for growth factors where release is modulated by focused ultrasound (FUS), specifically a mechanism termed acoustic droplet vaporization. With these fibrin-based, acoustically-responsive scaffolds (ARSs), release of a growth factor is non-invasively and spatiotemporally-controlled in an on-demand manner using non-thermal FUS. In vitro studies demonstrated sustained release of basic fibroblast growth factor (bFGF) from the ARSs using repeated applications of FUS. In in vivo studies, ARSs containing bFGF were implanted in mice following induction of hind limb ischemia, a preclinical model of CLI. During the 4-week study, mice in the ARS + FUS group longitudinally exhibited significantly more perfusion and less visible necrosis compared to other experimental groups. Additionally, significantly greater angiogenesis and less fibrosis were observed for the ARS + FUS group. Overall, these results highlight a promising, FUS-based method of delivering a pro-angiogenic growth factor for stimulating angiogenesis and reperfusion in a cardiovascular disease model. More broadly, these results could be used to personalize the delivery of therapeutics in different regenerative applications by actively controlling the release of a growth factor.


Assuntos
Fibrina , Fator 2 de Crescimento de Fibroblastos , Animais , Membro Posterior , Hidrogéis , Isquemia/terapia , Camundongos , Neovascularização Fisiológica , Volatilização
7.
Eur J Vasc Endovasc Surg ; 62(4): 590-596, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34465536

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the influence of inframalleolar disease (Global Limb Anatomic Staging System Inframalleolar [GLASS IM] modifier) on long term outcomes of patients with chronic limb threatening ischaemia (CLTI) after distal bypass. METHODS: Patients who underwent distal bypass for CLTI from January 2012 to December 2019 at a single centre were reviewed retrospectively. Comparisons including baseline characteristics, procedural details, and long term outcomes were made between patients with an intact pedal arch (GLASS IM modifier P0), an absent or severely diseased pedal arch (P1), and no target artery crossing the ankle into the foot (P2), diagnosed by pre- and intra-operative high quality angiography. The primary endpoint was limb salvage. The secondary endpoints were graft patency and wound healing. RESULTS: A total of 254 distal bypasses were performed in 206 patients (139 males; median age, 76 years). The GLASS IM modifier was P0 in 80 (32%) limbs, P1 in 127 (50%), and P2 in 47 (18%). During the follow up period, 22 limbs (9%) required major amputation. The limb salvage rates at three years in P0, P1, and P2 cases were 94%, 89%, and 93%, respectively, with no significant differences among the modifiers. The primary patencies at three years in P0, P1, and P2 cases were 49%, 38% and 24%, respectively. The primary patency in P2 cases was significantly lower than that in P0 cases (p < .050). The respective wound healing rates at 12 months were 97%, 93%, and 79%, and again the wound healing rate in P2 cases was significantly lower than those in other cases (p < .050). CONCLUSION: Long term outcomes including patency, limb salvage, and wound healing after distal bypass for CLTI patients with an infrapopliteal lesion were acceptable in cases in each GLASS IM modifier.


Assuntos
Angiografia , Isquemia/terapia , Doença Arterial Periférica/terapia , Veia Safena/transplante , Enxerto Vascular , Idoso , Idoso de 80 Anos ou mais , Amputação , Doença Crônica , Feminino , Humanos , Isquemia/diagnóstico por imagem , Isquemia/fisiopatologia , Salvamento de Membro , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Enxerto Vascular/efeitos adversos , Grau de Desobstrução Vascular , Cicatrização
8.
Trials ; 22(1): 595, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488845

RESUMO

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Noma , Tecido Adiposo , Animais , Ensaios Clínicos Fase II como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Método Duplo-Cego , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
9.
Ann Surg ; 274(4): 621-626, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506317

RESUMO

OBJECTIVE: The National Health Service demonstrated that regions of the United Kingdom with the highest number of patients enrolled in research studies had the lowest risk-adjusted mortality when patients were admitted to the hospital. Our goal was to investigate if this correlation was evident for patients with chronic limb threatening ischemia (CLI) treated in the United States (US). Accordingly, we examined correlations among sites participating in the Best Endovascular versus best Surgical Therapy in patients with Critical (BEST-CLI) trial, a multicenter, National Institute of Health-sponsored, international randomized controlled trial (RCT) comparing revascularization strategies in patients with CLI, and regional rates of major amputation from CLI. METHODS: We measured regional participation in the BEST-CLI trial by evaluating trial participation and enrollment rosters. To determine regional rates of lower limb amputation, we queried the Medicare database (2007-2016) for patients with concurrent peripheral arterial disease (PAD) and diabetes, then assessed how many had lower extremity amputations. Correlation of regional amputation rates with distribution of BEST-CLI sites in four US geographical regions was calculated using Pearson's correlation coefficients. Simple regression equations were used to calculate the significance of these correlation coefficients. RESULTS: Of 9,231,909 CLI patients, 342,406 underwent amputation in the Medicare dataset. Amputation rates per 1000 CLI patients differed by region (South 40.42, Midwest 40.12, West 34.81, Northeast 31.14). There were 116 US vascular centers, selected by volume and expertise that participated in BEST-CLI with the following distribution: South (n = 30, 26%), Midwest (n = 26, 22%), West (n = 29, 25%), and Northeast (n = 31, 27%). There was a negative correlation between the number of amputations per 1000 for Medicare CLI patients with diabetes and PAD and the number of BEST-CLI sites in the region which trended toward significance (Pearson R= -0.61, P = 0.39). CONCLUSIONS: Amputation rate among Medicare CLI patients is inversely correlated with US BEST-CLI site distribution. Higher participation in clinical research, especially within large RCTs, may be a marker of optimal PAD management.


Assuntos
Amputação/estatística & dados numéricos , Isquemia/terapia , Salvamento de Membro/estatística & dados numéricos , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/terapia , Sujeitos da Pesquisa/estatística & dados numéricos , Idoso , Procedimentos Endovasculares/estatística & dados numéricos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos
10.
Ophthalmologe ; 118(11): 1099-1106, 2021 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-34535826

RESUMO

BACKGROUND: Acute central retinal artery occlusion (CRAO) represents an ophthalmological emergency with neurological implications, which must be immediately investigated and treated. Intravenous thrombolysis could improve the prognosis only within the first 4.5 h due to limited retinal tolerance to ischemia. Accordingly, ophthalmological acute diagnostics should be reduced to the minimum necessary followed by immediate referral to a clinic with neurovascular expertise. The typical anamnesis is well-suited for triaging and should be carried out ín a standardized way in order to determine the onset of symptoms as exactly as possible. In addition to pathognomic findings in fundoscopy, there are characteristic ischemia-related changes in optical coherence tomography (OCT), which document ischemia in the inner retina and under some circumstances can provide inferences for the onset of ischemia. OBJECTIVE: This review article summarizes the acute ophthalmological diagnostic management of acute CRAO with a focus on the typical OCT and transorbital ultrasound (TOUS) findings and discusses their potential use as ischemic biomarkers. CONCLUSION: Characteristic biomarkers make OCT an important diagnostic tool in the management of acute CRAO. Additional information can be obtained by TOUS. With an evidence-based treatment established in the future both tools could be used for indications for treatment and for estimating the prognosis.


Assuntos
Oclusão da Artéria Retiniana , Biomarcadores , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Retina , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/terapia , Tomografia de Coerência Óptica
11.
World J Gastroenterol ; 27(29): 4746-4762, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34447224

RESUMO

Ischemic bowel disease (ISBODI) includes colon ischemia, acute mesenteric ischemia (AMI) and chronic mesenteric ischemia (CMI). Epidemiologically, colon ischemia is the most common type followed by AMI and CMI. There are various risk factors for the development of ISBODI. Abdominal pain is the common presenting symptom of each type. High clinical suspicion is essential in ordering appropriate tests. Imaging studies and colonoscopy with biopsy are the main diagnostic tests. Treatment varies from conservative measures to surgical resection and revascularization. Involvement of multidisciplinary team is essential in managing ISBODI. Although open surgery with revascularization plays an important role, recently there is an increasing interest in percutaneous endovascular treatment.


Assuntos
Colite Isquêmica , Procedimentos Endovasculares , Isquemia Mesentérica , Oclusão Vascular Mesentérica , Doença Aguda , Doença Crônica , Humanos , Isquemia/etiologia , Isquemia/terapia , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/epidemiologia , Isquemia Mesentérica/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
12.
Eur J Vasc Endovasc Surg ; 62(4): 583-589, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34334314

RESUMO

OBJECTIVE: The aim of this study was to evaluate changes in transcutaneous oxygen pressure (tcpO2) and systolic toe pressure (TP) during endovascular intervention. METHODS: This was a single centre prospective, non-randomised, observational feasibility study. Patients with chronic limb threatening ischaemia (CLTI) due to infrainguinal disease scheduled for endovascular treatment were included between March 2018 and December 2019. TcpO2 was measured continuously bilaterally at foot level throughout the procedure and at follow up. Specific time points during the intervention were chosen for comparison to baseline (before arterial puncture): average tcpO2 level five minutes prior to percutaneous transluminal angioplasty (PTA); 10 minutes after PTA; and at completion. Bilateral TP was recorded using laser Doppler flowmetry before arterial puncture, at completion, and at clinical follow up. Angiograms were analysed for successful revascularisation and vascular lesions classified according to the Global Limb Anatomical Scoring System (GLASS). Rutherford and WIfI (Wound, Ischaemia, and foot Infection) classifications were registered, as well as clinical outcome. RESULTS: Twenty-one patients completed the study. Completion angiograms showed inline flow to the foot in all but two patients. Median time to follow up was 10 weeks (range 8 - 13 weeks) and all patients except one improved clinically. TcpO2 decreased during the initial stage of the intervention, from before arterial puncture to five minute average before PTA (p < .001) and did not recover to above baseline values at the end of intervention. TcpO2 increased significantly at follow up (p < .001). TP increased statistically significantly during intervention (p < .001) and at follow up (p < .001) compared with baseline. CONCLUSION: TcpO2 and TP measurements are safe and feasible non-invasive techniques for haemodynamic monitoring during endovascular revascularisation. TP increased significantly immediately after completion of the successful intervention, whereas tcpO2 did not. Both TP and tcpO2 demonstrated a significant increase at the 10 week follow up.


Assuntos
Monitorização Transcutânea dos Gases Sanguíneos , Determinação da Pressão Arterial , Pressão Sanguínea , Procedimentos Endovasculares , Isquemia/terapia , Oxigênio/sangue , Doença Arterial Periférica/terapia , Dedos do Pé/irrigação sanguínea , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Procedimentos Endovasculares/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Isquemia/diagnóstico , Isquemia/fisiopatologia , Masculino , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
13.
Stem Cell Res Ther ; 12(1): 456, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384486

RESUMO

BACKGROUND: The efficacy of stem cell therapy for ischemia repair has been limited by low cell retention rate. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-ß super family, which has multiple effects on development, physiology and diseases. The objective of the study is to investigate whether GDF11 could affect the efficacy of stem cell transplantation. METHODS: We explored the effects of GDF11 on proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy in vitro and in vivo. RESULTS: Mouse bone marrow-derived MSCs were transduced with lentiviral vector to overexpress GDF11 (MSCGDF11). After exposed to hypoxia and serum deprivation for 48 h, MSCGDF11 were significantly better in viability than control MSCs (MSCvector). MSCGDF11 also had higher mobility and better angiogenic paracrine effects. The cytokine antibody array showed more angiogenic cytokines in the conditioned medium of MSCGDF11 than that of MSCvector, such as epidermal growth factor, platelet-derived growth factor-BB, placenta growth factor. When MSCs (1 × 106 cells in 50 µl) were injected into ischemic hindlimb of mice after femoral artery ligation, MSCGDF11 had higher retention rate in the muscle than control MSCs. Injection of MSCGDF11 resulted in better blood reperfusion and limb salvage than that of control MSCs after 14 days. Significantly more CD31+ endothelial cells and α-SMA + smooth muscle cells were detected in the ischemic muscles that received MSCGDF11. The effects of GDF11 were through activating TGF-ß receptor and PI3K/Akt signaling pathway. CONCLUSION: Our study demonstrated an essential role of GDF11 in promoting therapeutic functions of MSCs for ischemic diseases by enhancing MSC viability, mobility, and angiogenic paracrine functions.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Proteínas Morfogenéticas Ósseas , Células Cultivadas , Células Endoteliais , Feminino , Fatores de Diferenciação de Crescimento/genética , Isquemia/terapia , Camundongos , Neovascularização Fisiológica , Fosfatidilinositol 3-Quinases , Gravidez
14.
PLoS One ; 16(8): e0255075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34375370

RESUMO

Induced endothelial cells (iECs) generated from neonatal fibroblasts via transdifferentiation have been shown to have pro-angiogenic properties and are a potential therapy for peripheral arterial disease (PAD). It is unknown if iECs can be generated from fibroblasts collected from PAD patients and whether these cells are pro-angiogenic. In this study fibroblasts were collected from four PAD patients undergoing carotid endarterectomies. These cells, and neonatal fibroblasts, were transdifferentiated into iECs using modified mRNA. Endothelial phenotype and pro-angiogenic cytokine secretion were investigated. NOD-SCID mice underwent surgery to induce hindlimb ischaemia in a murine model of PAD. Mice received intramuscular injections with either control vehicle, or 1 × 106 neonatal-derived or 1 × 106 patient-derived iECs. Recovery in perfusion to the affected limb was measured using laser Doppler scanning. Perfusion recovery was enhanced in mice treated with neonatal-derived iECs and in two of the three patient-derived iEC lines investigated in vivo. Patient-derived iECs can be successfully generated from PAD patients and for specific patients display comparable pro-angiogenic properties to neonatal-derived iECs.


Assuntos
Células Endoteliais/patologia , Fibroblastos/patologia , Neovascularização Fisiológica , Doença Arterial Periférica/patologia , Acetilação/efeitos dos fármacos , Animais , Capilares/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Colágeno/farmacologia , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Combinação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/transplante , Fibroblastos/efeitos dos fármacos , Membro Posterior/irrigação sanguínea , Membro Posterior/patologia , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Isquemia/patologia , Isquemia/terapia , Laminina/farmacologia , Lipoproteínas LDL/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neovascularização Fisiológica/efeitos dos fármacos , Perfusão , Lectinas de Plantas/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteoglicanas/farmacologia
15.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34359994

RESUMO

Mitochondria are key players of aerobic respiration and the production of adenosine triphosphate and constitute the energetic core of eukaryotic cells. Furthermore, cells rely upon mitochondria homeostasis, the disruption of which is reported in pathological processes such as liver hepatotoxicity, cancer, muscular dystrophy, chronic inflammation, as well as in neurological conditions including Alzheimer's disease, schizophrenia, depression, ischemia and glaucoma. In addition to the well-known spontaneous cell-to-cell transfer of mitochondria, a therapeutic potential of the transplant of isolated, metabolically active mitochondria has been demonstrated in several in vitro and in vivo experimental models of disease. This review explores the striking outcomes achieved by mitotherapy thus far, and the most relevant underlying data regarding isolated mitochondria transplantation, including mechanisms of mitochondria intake, the balance between administration and therapy effectiveness, the relevance of mitochondrial source and purity and the mechanisms by which mitotherapy is gaining ground as a promising therapeutic approach.


Assuntos
Doença de Alzheimer/terapia , Depressão/terapia , Glaucoma/terapia , Hepatite/terapia , Isquemia/terapia , Mitocôndrias/transplante , Distrofias Musculares/terapia , Neoplasias/terapia , Esquizofrenia/terapia , Trifosfato de Adenosina/biossíntese , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Depressão/genética , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Glaucoma/genética , Glaucoma/metabolismo , Glaucoma/patologia , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Humanos , Isquemia/genética , Isquemia/metabolismo , Isquemia/patologia , Fígado/metabolismo , Fígado/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação Oxidativa , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Resultado do Tratamento
16.
Rev Assoc Med Bras (1992) ; 67(2): 213-217, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34406244

RESUMO

OBJECTIVE: To investigate the efficacy of a short-term application of Transcutaneous Electric Nerve Stimulation to relieve rest pain in patients with chronic limb-threatening ischemia. METHODS: In patients ³18 years old, with chronic limb-threatening ischemia and rest pain ³3 in the Visual Analogue Scale, without diabetic neuropathy were randomly assigned to 1) Transcutaneous Electric Nerve Stimulation (100 Hz, 200 µs) or 2) sham intervention, both during one or two 20 min treatment sessions. The primary outcome was pain intensity, assessed by the visual analogue scale (0-10 cm) and described by the McGill Pain Questionnaire. We used a t-test for difference of means. RESULTS: A total of 169 patients were assessed, 23 met the study criteria and were randomized. Thirty-four applications were performed in two days: in the 17 Transcutaneous Nerve Stimulation and 17 sham. The within-group analysis indicated a pain decrease in both groups (Transcutaneous Electric Nerve Stimulation, from 7-3.9 cm, p<0.0001, and sham from 5.8-3.2 cm, p<0.0001). No statistically significant difference was verified between-groups (p=0.5). CONCLUSIONS: Both groups showed a decrease in rest pain of 54 and 55%, respectively. However, there was no difference between short-term high-frequency Transcutaneous Electric Nerve Stimulation and sham intervention to relieve ischemic rest pain in chronic limb-threatening ischemia patients.


Assuntos
Estimulação Elétrica Nervosa Transcutânea , Humanos , Pacientes Internados , Isquemia/terapia , Dor , Medição da Dor , Resultado do Tratamento
17.
Br J Radiol ; 94(1125): 20210215, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233490

RESUMO

OBJECTIVES: To emerge hypoperfusion of lower limbs in patients with critical limb ischemia (CLI) using Intravoxel Incoherent Motion microperfusion magnetic resonance imaging (IVIM-MRI). Moreover to examine the ability of IVIM-MRI to differentiate patients with severe peripheral arterial disease (PAD) from normal subjects and evaluate the percutaneous transluminal angioplasty (PTA) results in patients with CLI. METHODS: Eight patients who presented with CLI and six healthy volunteers were examined. The patients underwent IVIM-MRI of lower extremity before and following PTA. The imaging protocol included sagittal diffusion-weighted (DW) sequences. DW images were analyzed and color parametric maps of the micro-circulation of blood inside the capillary network (D*) were constructed. The studies were evaluated by two observers to define interobserver reproducibility. RESULTS: Technical success was achieved in all patients (8/8). The mean ankle-brachial index increased from 0.35 ± 0.2 to 0.76 ± 0.25 (p < 0.05). Successful revascularization improved IVIM microperfusion. Mean D* increased from 279.88 ± 13.47 10-5 mm2/s to 331.51 ± 31 10-5 mm2/s, following PTA, p < 0.05. Moreover, PAD patients presented lower D* values as compared to healthy individuals (279.88 ± 13.47 10-5 mm2/s vs 332.47 ± 22.95 10-5 mm2/s, p < 0.05, respectively). Good interobserver agreement was obtained with an ICC = 0.84 (95% CI 0.64-0.93). CONCLUSIONS: IVIM-MRI can detect differences in microperfusion between patients with PAD and healthy individuals. Moreover, significant restitution of IVIM microperfusion is found following successful PTA. ADVANCES IN KNOWLEDGE: IVIM-MRI is a safe, reproducible and effective modality for evaluation of lower limb hypoperfusion in patients with PAD. It seems also to be a helpful tool to detect changes of tissue perfusion in patients with CLI following revascularization.


Assuntos
Angioplastia/métodos , Pé/irrigação sanguínea , Isquemia/diagnóstico por imagem , Isquemia/terapia , Imageamento por Ressonância Magnética/métodos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Adulto , Idoso , Índice Tornozelo-Braço/métodos , Estudos de Viabilidade , Feminino , Pé/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes
18.
Eur J Vasc Endovasc Surg ; 62(3): 463-468, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303599

RESUMO

OBJECTIVE: Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. METHODS: In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life. RESULTS: The study included 20 patients (16 men; median age 68.0 years; range, 50.0 - 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 - 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 - 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. CONCLUSION: Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.


Assuntos
Fibrinolíticos/administração & dosagem , Isquemia/terapia , Microbolhas , Doença Arterial Periférica/terapia , Terapia Trombolítica , Terapia por Ultrassom , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Isquemia/diagnóstico por imagem , Isquemia/fisiopatologia , Masculino , Microbolhas/efeitos adversos , Pessoa de Meia-Idade , Países Baixos , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/fisiopatologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Terapia por Ultrassom/efeitos adversos , Grau de Desobstrução Vascular
19.
Mol Ther ; 29(10): 3042-3058, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34332145

RESUMO

Reprogramming non-cardiomyocytes (non-CMs) into cardiomyocyte (CM)-like cells is a promising strategy for cardiac regeneration in conditions such as ischemic heart disease. Here, we used a modified mRNA (modRNA) gene delivery platform to deliver a cocktail, termed 7G-modRNA, of four cardiac-reprogramming genes-Gata4 (G), Mef2c (M), Tbx5 (T), and Hand2 (H)-together with three reprogramming-helper genes-dominant-negative (DN)-TGFß, DN-Wnt8a, and acid ceramidase (AC)-to induce CM-like cells. We showed that 7G-modRNA reprogrammed 57% of CM-like cells in vitro. Through a lineage-tracing model, we determined that delivering the 7G-modRNA cocktail at the time of myocardial infarction reprogrammed ∼25% of CM-like cells in the scar area and significantly improved cardiac function, scar size, long-term survival, and capillary density. Mechanistically, we determined that while 7G-modRNA cannot create de novo beating CMs in vitro or in vivo, it can significantly upregulate pro-angiogenic mesenchymal stromal cells markers and transcription factors. We also demonstrated that our 7G-modRNA cocktail leads to neovascularization in ischemic-limb injury, indicating CM-like cells importance in other organs besides the heart. modRNA is currently being used around the globe for vaccination against COVID-19, and this study proves this is a safe, highly efficient gene delivery approach with therapeutic potential to treat ischemic diseases.


Assuntos
Reprogramação Celular/genética , Terapia Genética/métodos , Isquemia/terapia , Músculo Esquelético/irrigação sanguínea , Infarto do Miocárdio/terapia , Neovascularização Fisiológica/genética , Regeneração/genética , Transfecção/métodos , Animais , Animais Recém-Nascidos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout para ApoE , Miócitos Cardíacos/metabolismo , RNA Mensageiro/genética
20.
Pediatr Rheumatol Online J ; 19(1): 104, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193201

RESUMO

BACKGROUND: H syndrome (HS) is a rare autoinflammatory disease caused by a mutation in the solute carrier family 29, member 3 (SCL29A3) gene. It has a variable clinical presentation and little phenotype-genotype correlation. The pathognomonic sign of HS is cutaneous hyperpigmentation located mainly in the inner thighs and often accompanied by other systemic manifestations. Improvement after tocilizumab treatment has been reported in a few patients with HS. We report the first patient with HS who presented cardiogenic shock, multiorgan infiltration, and digital ischemia. CASE PRESENTATION: 8-year-old boy born to consanguineous parents of Moroccan origin who was admitted to the intensive care unit during the Coronavirus Disease-2019 (COVID-19) pandemic with tachypnoea, tachycardia, and oliguria. Echocardiography showed dilated cardiomyopathy and severe systolic dysfunction compatible with cardiogenic shock. Additionally, he presented with multiple organ dysfunction syndrome. SARS-CoV-2 polymerase chain reaction (PCR) and antibody detection by chromatographic immunoassay were negative. A previously ordered gene panel for pre-existing sensorineural hearing loss showed a pathological mutation in the SCL29A3 gene compatible with H syndrome. Computed tomography scan revealed extensive alveolar infiltrates in the lungs and multiple poor defined hypodense lesions in liver, spleen, and kidneys; adenopathy; and cardiomegaly with left ventricle subendocardial nodules. Invasive mechanical ventilation, broad antibiotic and antifungal coverage showed no significant response. Therefore, Tocilizumab as compassionate use together with pulsed intravenous methylprednisolone was initiated. Improvement was impressive leading to normalization of inflammation markers, liver and kidney function, and stabilising heart function. Two weeks later, he was discharged and has been clinically well since then on two weekly administration of Tocilizumab. CONCLUSIONS: We report the most severe disease course produced by HS described so far in the literature. Our patient's manifestations included uncommon, new complications such as acute heart failure with severe systolic dysfunction, multi-organ cell infiltrate, and digital ischemia. Most of the clinical symptoms of our patient could have been explained by SARS-CoV-2, demonstrating the importance of a detailed differential diagnosis to ensure optimal treatment. Although the mechanism of autoinflammation of HS remains uncertain, the good response of our patient to Tocilizumab makes a case for the important role of IL-6 in this syndrome and for considering Tocilizumab as a first-line treatment, at least in severely affected patients.


Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Isquemia/fisiopatologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Choque Cardiogênico/fisiopatologia , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19 , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/terapia , Criança , Glucocorticoides/uso terapêutico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Isquemia/terapia , Nefropatias/diagnóstico por imagem , Nefropatias/fisiopatologia , Nefropatias/terapia , Hepatopatias/diagnóstico por imagem , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Pneumopatias/diagnóstico por imagem , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Linfadenopatia/diagnóstico por imagem , Linfadenopatia/fisiopatologia , Linfadenopatia/terapia , Masculino , Metilprednisolona/uso terapêutico , Insuficiência de Múltiplos Órgãos/terapia , Proteínas de Transporte de Nucleosídeos/genética , Pulsoterapia , Respiração Artificial , SARS-CoV-2 , Choque Cardiogênico/terapia , Esplenopatias/diagnóstico por imagem , Esplenopatias/fisiopatologia , Esplenopatias/terapia , Dedos do Pé/irrigação sanguínea , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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