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1.
Artigo em Inglês | MEDLINE | ID: mdl-31922362

RESUMO

Therapeutic angiogenesis, that is, the generation of new vessels by delivery of specific factors, is required both for rapid vascularization of tissue-engineered constructs and to treat ischemic conditions. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis. However, uncontrolled expression can lead to aberrant vascular growth and vascular tumors (angiomas). Major challenges to fully exploit VEGF potency for therapy include the need to precisely control in vivo distribution of growth factor dose and duration of expression. In fact, the therapeutic window of VEGF delivery depends on its amount in the microenvironment around each producing cell rather than on the total dose, since VEGF remains tightly bound to extracellular matrix (ECM). On the other hand, short-term expression of less than about 4 weeks leads to unstable vessels, which promptly regress following cessation of the angiogenic stimulus. Here, we will briefly overview some key aspects of the biology of VEGF and angiogenesis and discuss their therapeutic implications with a particular focus on approaches using gene therapy, genetically modified progenitors, and ECM engineering with recombinant factors. Lastly, we will present recent insights into the mechanisms that regulate vessel stabilization and the switch between normal and aberrant vascular growth after VEGF delivery, to identify novel molecular targets that may improve both safety and efficacy of therapeutic angiogenesis.

2.
Infect Control Hosp Epidemiol ; 40(12): 1374-1379, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619300

RESUMO

BACKGROUND: Surgical site infections (SSIs) are common surgical complications that lead to increased costs. Depending on payer type, however, they do not necessarily translate into deficits for every hospital. OBJECTIVE: We investigated how surgical site infections (SSIs) influence the contribution margin in 2 reimbursement systems based on diagnosis-related groups (DRGs). METHODS: This preplanned observational health cost analysis was nested within a Swiss multicenter randomized controlled trial on the timing of preoperative antibiotic prophylaxis in general surgery between February 2013 and August 2015. A simulation of cost and income in the National Health Service (NHS) England reimbursement system was conducted. RESULTS: Of 5,175 patients initially enrolled, 4,556 had complete cost and income data as well as SSI status available for analysis. SSI occurred in 228 of 4,556 of patients (5%). Patients with SSIs were older, more often male, had higher BMIs, compulsory insurance, longer operations, and more frequent ICU admissions. SSIs led to higher hospital cost and income. The median contribution margin was negative in cases of SSI. In SSI cases, median contribution margin was Swiss francs (CHF) -2045 (IQR, -12,800 to 4,848) versus CHF 895 (IQR, -2,190 to 4,158) in non-SSI cases. Higher ASA class and private insurance were associated with higher contribution margins in SSI cases, and ICU admission led to greater deficits. Private insurance had a strong increasing effect on contribution margin at the 10th, 50th (median), and 90th percentiles of its distribution, leading to overall positive contribution margins for SSIs in Switzerland. The NHS England simulation with 3,893 patients revealed similar but less pronounced effects of SSI on contribution margin. CONCLUSIONS: Depending on payer type, reimbursement systems with DRGs offer only minor financial incentives to the prevention of SSI.

3.
World J Surg ; 43(10): 2420-2425, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292675

RESUMO

BACKGROUND: Long-duration surgery requires repeated administration of antimicrobial prophylaxis (amp). Amp "redosing" reduces incidence of surgical site infections (SSI) but is frequently omitted. Clinical relevance of redosing timing needs to be investigated. Here, we evaluated the effects of compliance with amp redosing and its timing on SSI incidence in prolonged duration surgery. METHODS: Data from >9000 patients undergoing visceral, trauma, or vascular surgery with elective or emergency treatment in two tertiary referral Swiss hospitals were analyzed. All patients had to receive amp preoperatively and redosing, if indicated. Antibiotics used were cefuroxime (1.5 or 3 g, if weight >80 kg), or cefuroxime and metronidazole (1.5 and 0.5 g, or 3 and 1 g doses, if weight >80 kg). Alternatively, in cases of known or suspected allergies, vancomycin (1 g), gentamicin (4 mg/Kg), and metronidazole or clindamycin (300 mg) with or without ciprofloxacin (400 mg) were used. Association of defined parameters, including wound class, ASA scores, and duration of operation, with SSI incidence was explored. RESULTS: In the whole cohort, SSI incidence significantly correlated with duration of surgery (ρ = 0.73, p = 0.031). In 593 patients undergoing >240 min long interventions, duration of surgery was the only parameter significantly (p < 0.001) associated with increased SSI risk, whereas wound class, ASA scores, treatment areas, and emergency versus elective hospital entry were not. Redosing significantly reduced SSI incidence as shown by multivariate analysis (OR 0.60, 95% CI 0.37-0.96, p = 0.034), but exact timing had no significant impact. CONCLUSIONS: Long-duration surgery associates with higher SSI incidence. Irrespective of its exact timing, amp redosing significantly decreases SSI risk.

4.
J Vasc Surg ; 70(1): 216-223, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30922743

RESUMO

OBJECTIVE: Noncardiac surgery early after coronary stenting has been associated with a high rate of stent thrombosis and catastrophic outcomes. However, those outcomes were mostly seen when dual antiplatelet therapy (DAPT) was discontinued before surgery. This observational study sought to estimate the risk of major adverse cardiac events (MACEs) after femoral artery repair following recent stent-percutaneous coronary intervention under continued DAPT and to explore potential risk factors. We suspect that in this setting, the risk of MACEs is lower than previously reported. METHODS: This retrospective cohort study included all consecutive patients who underwent femoral artery repair because of puncture site complications (bleeding or occlusion) within 28 days after coronary stenting at a tertiary referral center in Switzerland from 2005 to 2015. The primary end point consisted of the MACEs death, cardiac arrest, stent thrombosis, and myocardial infarction. RESULTS: There were 12,960 patients who underwent coronary stenting. Seventy patients (0.5%) required repair of the femoral vessels, which was performed under continued DAPT in all cases. Eight patients (11.4%; 95% confidence interval [CI], 5.4-21.8) experienced a total of 17 MACEs within 30 days after surgery, including 5 deaths (7.1%; 95% CI, 2.7-16.6). Factors significantly associated with postoperative MACEs were cardiogenic shock on admission before coronary stenting (hazard ratio, 6.9; 95% CI, 1.8-29.6; P = .035) and limb ischemia as an indication for surgery compared with bleeding (hazard ratio, 10.5; 95% CI, 2.7-40.7; P = .008). CONCLUSIONS: In our series, femoral artery repair under DAPT for access site complications early after stent-percutaneous coronary intervention is associated with only a modest MACE rate and therefore a much better outcome than previously reported.

5.
BMC Cancer ; 19(1): 41, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621641

RESUMO

BACKGROUND: The Rearranged during Transfection (RET) protein is overexpressed in a subset of Estrogen Receptor (ER) positive breast cancer, with both signalling pathways functionally interacting. This cross-talk plays a pivotal role in the resistance of breast cancer cells to anti-endocrine therapies, and RET expression is assumed to correlate with poor prognosis based on findings in small patient cohorts. The aim of our study was to investigate the impact of RET expression on patient outcome in human breast cancer. METHODS: We performed an immunohistochemical analysis of RET protein expression on a tissue microarray encompassing 990 breast cancer patients and correlated its expression with clinicopathological parameters and survival data. RESULTS: Expression of RET was detected in 409 out of 990 cases (41.3%). RET and ER expression significantly correlated (p < 0.0001). The Luminal B HER2-positive subtype showed the highest expression rate (48.9%). In univariate and multivariate survival analyses, RET expression had no impact on overall survival. CONCLUSION: We confirmed the co-expression of RET and ER, but we did not find RET expression to be an independent prognostic factor in human breast cancer. Clinical trials with newly developed RET inhibitors are needed to evaluate if RET inhibition has a beneficial impact on patient survival in ER positive breast cancer.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Transdução de Sinais/genética , Tamoxifeno/administração & dosagem
6.
Am J Surg ; 217(1): 17-23, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935905

RESUMO

BACKGROUND: Surgical drains are widely used despite limited evidence in their favor. This study describes the associations between drains and surgical site infections (SSI). METHODS: This prospective observational double center study was performed in Switzerland between February 2013 and August 2015. RESULTS: The odds of SSI in the presence of drains were increased in general (OR 2.41, 95%CI 1.32-4.30, p = 0.004), but less in vascular and not in orthopedic trauma surgery. In addition to the surgical division, the association between drains and SSI depended significantly on the duration of surgery (p = 0.01) and wound class (p = 0.034). Furthermore, the duration of drainage (OR 1.24, 95%CI 1.15-1.35, p < 0.001), the number (OR 1.74, 95%CI 1.09-2.74, p = 0.019) and type of drains (open versus closed: OR 3.68, 95%CI 1.88, 6.89, p < 0.001) as well as their location (overall p = 0.002) were significantly associated with SSI. CONCLUSIONS: The general use of drains is discouraged. However, drains may be beneficial in specific surgical procedures.


Assuntos
Drenagem/estatística & dados numéricos , Infecção da Ferida Cirúrgica/epidemiologia , Adulto , Idoso , Drenagem/efeitos adversos , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Duração da Cirurgia , Estudos Prospectivos , Fatores de Risco , Suíça
7.
Am J Surg ; 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31910989

RESUMO

BACKGROUND/AIM: To investigate whether teaching procedures and surgical experience are associated with surgical site infection (SSI) rates. METHODS: This prospective cohort study of patients undergoing general, orthopedic trauma and vascular surgery procedures was done between 2012 and 2015 at two tertiary care hospitals in Switzerland/Europe. RESULTS: Out of a total of 4560 patients/surgeries, 1403 (30.8%) were classified as teaching operations. The overall SSI rate was 5.1% (n = 233). Teaching operations (OR 0.78, 95% CI 0.57-1.07, p = 0.120), junior surgeons (OR 0.80, 95% CI 0.55-1.15, p = 0.229) and surgical experience (OR 0.997, 95% CI 0.982-1.012, p = 0.676) were overall not independently associated with the odds of SSI. However, for surgeons' seniority and experience, these associations depended on the duration of surgery. CONCLUSIONS: In procedures of shorter and medium duration, teaching procedures and junior as well as less experienced surgeons are not independently associated with increased odds of SSI.

8.
World J Surg ; 42(12): 3888-3896, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29978247

RESUMO

BACKGROUND: Surgical site infections (SSI) are a major cause of morbidity and mortality in surgical patients. Postoperative and total hospital length of stay (LOS) are known to be prolonged by the occurrence of SSI. Preoperative LOS may increase the risk of SSI. This study aims at identifying the associations of pre- and postoperative LOS in hospital and intensive care with the occurrence of SSI. METHODS: This observational cohort study includes general, orthopedic trauma and vascular surgery patients at two tertiary referral centers in Switzerland between February 2013 and August 2015. The outcome of interest was the 30-day SSI rate. RESULTS: We included 4596 patients, 234 of whom (5.1%) experienced SSI. Being admitted at least 1 day before surgery compared to same-day surgery was associated with a significant increase in the odds of SSI in univariate analysis (OR 1.65, 95% CI 1.25-2.21, p < 0.001). More than 1 day compared to 1 day of preoperative hospital stay did not further increase the odds of SSI (OR 1.08, 95% CI 0.77-1.50, p = 0.658). Preoperative admission to an intensive care unit (ICU) increased the odds of SSI as compared to hospital admission outside of an ICU (OR 2.19, 95% CI 0.89-4.59, p = 0.057). Adjusting for potential confounders in multivariable analysis weakened the effects of both preoperative admission to hospital (OR 1.38, 95% CI 0.99-1.93, p = 0.061) and to the ICU (OR 1.89, 95% CI 0.73-4.24, p = 0.149). CONCLUSION: There was no significant independent association between preoperative length of stay and risk of SSI while SSI and postoperative LOS were significantly associated.


Assuntos
Tempo de Internação/estatística & dados numéricos , Período Pós-Operatório , Período Pré-Operatório , Infecção da Ferida Cirúrgica/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Suíça/epidemiologia , Centros de Atenção Terciária
9.
Ther Umsch ; 75(8): 471-477, 2018.
Artigo em Alemão | MEDLINE | ID: mdl-31038042

RESUMO

Aortic aneurysms - epidemiology and therapeutic options Abstract. Aortic aneurysms can arise in any part of the aorta between its root and its bifurcation. Men over the age of 65 are most commonly affected while the prevalence increases with age. Risk factors are identical with those for any atherosclerotic disease. Treatment is always invasive while its indication depends on the expected risk of rupture (which in turn depends on the maximum diameter) and the risk of the treatment itself. While perioperative mortality rates are significantly lower after endovascular than after open aneurysm repair, long-term mortality rates are not.


Assuntos
Aneurisma Aórtico , Implante de Prótese Vascular , Procedimentos Endovasculares , Aneurisma Aórtico/epidemiologia , Aneurisma Aórtico/cirurgia , Aneurisma da Aorta Abdominal , Procedimentos Cirúrgicos Eletivos , Humanos , Masculino , Fatores de Risco , Resultado do Tratamento
10.
Am J Surg ; 215(4): 651-657, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28982517

RESUMO

BACKGROUND: Routine preoperative blood work is not recommended but selected biochemical markers may predict the risk of surgical site infection (SSI). This study examines the association between preoperative biochemical markers and the risk of SSI. METHODS: This observational cohort study, nested in a randomized controlled trial, was conducted at two tertiary referral centers in Switzerland. RESULTS: 122 (5.8%) of 2093 patients experienced SSI. Preoperative increasing levels of albumin (OR 0.93), CRP (OR 1.34), hemoglobin (OR 0.87) and eGFR (OR 0.90) were significantly associated with the odds of SSI. The same accounts for categorized parameters. The highest area under the curve from ROC curves was 0.62 for albumin. Positive predictive values ranged from 6.4% to 9.5% and negative predictive values from 94.8% to 95.7%. The association of CRP, mildly and moderately decreased eGFR and hemoglobin with the odds of SSI remained significant on multivariate analysis. CONCLUSIONS: Our results do not support generally delaying elective surgery based on preoperative blood results. However, it may be considered in situations with potentially severe sequelae of SSI.


Assuntos
Biomarcadores/sangue , Cuidados Pré-Operatórios , Infecção da Ferida Cirúrgica/sangue , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Suíça
11.
Lancet Infect Dis ; 17(6): 605-614, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28385346

RESUMO

BACKGROUND: Based on observational studies, administration of surgical antimicrobial prophylaxis (SAP) for the prevention of surgical site infection (SSI) is recommended within 60 min before incision. However, the precise optimum timing is unknown. This trial compared early versus late administration of SAP before surgery. METHODS: In this phase 3 randomised controlled superiority trial, we included general surgery adult inpatients (age ≥18 years) at two Swiss hospitals in Basel and Aarau. Patients were randomised centrally and stratified by hospital according to a pre-existing computer-generated list in a 1:1 ratio to receive SAP early in the anaesthesia room or late in the operating room. Patients and the outcome assessment team were blinded to group assignment. SAP consisted of single-shot, intravenous infusion of 1·5 g of cefuroxime, a commonly used cephalosporin with a short half-life, over 2-5 min (combined with 500 mg metronidazole in colorectal surgery). The primary endpoint was the occurrence of SSI within 30 days of surgery. The main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01790529. FINDINGS: Between Feb 21, 2013, and Aug 3, 2015, 5580 patients were randomly assigned to receive SAP early (2798 patients) or late (2782 patients). 5175 patients (2589 in the early group and 2586 in the late group) were analysed. Median administration time was 42 min before incision in the early group (IQR 30-55) and 16 min before incision in the late group (IQR 10-25). Inpatient follow-up rate was 100% (5175 of 5175 patients); outpatient 30-day follow-up rate was 88·8% (4596 of 5175), with an overall SSI rate of 5·1% (234 of 4596). Early administration of SAP did not significantly reduce the risk of SSI compared with late administration (odds ratio 0·93, 95% CI 0·72-1·21, p=0·601). INTERPRETATION: Our findings do not support any narrowing of the 60-min window for the administration of a cephalosporin with a short half-life, thereby obviating the need for increasingly challenging SAP timing recommendations. FUNDING: Swiss National Science Foundation, Hospital of Aarau, University of Basel, Gottfried und Julia Bangerter-Rhyner Foundation, Hippocrate Foundation, and Nora van Meeuwen-Häfliger Foundation.


Assuntos
Antibacterianos/uso terapêutico , Cefuroxima/uso terapêutico , Esquema de Medicação , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Idoso , Anti-Infecciosos/uso terapêutico , Feminino , Humanos , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
13.
Sci Rep ; 6: 21546, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26882992

RESUMO

Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive. The angiogenic master regulator VEGF-A can induce aberrant angiogenesis if expressed above a threshold level. Since VEGF remains localized in the matrix around expressing cells, homogeneous dose distribution in target tissues is required, which is challenging. We found that co-expression of the pericyte-recruiting factor PDGF-BB at a fixed ratio with VEGF from a single bicistronic vector ensured normal angiogenesis despite heterogeneous high VEGF levels. Taking advantage of a highly controlled gene delivery platform, based on monoclonal populations of transduced myoblasts, in which every cell stably produces the same amount of each factor, here we rigorously investigated a) the dose-dependent effects, and b) the long-term safety and stability of VEGF and PDGF-BB co-expression in skeletal muscle. PDGF-BB co-expression did not affect the normal angiogenesis by low and medium VEGF doses, but specifically prevented vascular tumors by high VEGF, yielding instead normal and mature capillary networks, accompanied by robust arteriole formation. Induced angiogenesis persisted unchanged up to 4 months, while no tumors appeared. Therefore, PDGF-BB co-expression is an attractive strategy to improve safety and efficacy of therapeutic angiogenesis by VEGF gene delivery.


Assuntos
Expressão Gênica , Vetores Genéticos/genética , Músculo Esquelético/metabolismo , Neovascularização Fisiológica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Becaplermina , Genes Reporter , Camundongos , Mioblastos/metabolismo , Mioblastos/transplante , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
14.
Trials ; 15: 188, 2014 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-24885132

RESUMO

BACKGROUND: Surgical site infections are the most common hospital-acquired infections among surgical patients. The administration of surgical antimicrobial prophylaxis reduces the risk of surgical site infections . The optimal timing of this procedure is still a matter of debate. While most studies suggest that it should be given as close to the incision time as possible, others conclude that this may be too late for optimal prevention of surgical site infections. A large observational study suggests that surgical antimicrobial prophylaxis should be administered 74 to 30 minutes before surgery. The aim of this article is to report the design and protocol of a randomized controlled trial investigating the optimal timing of surgical antimicrobial prophylaxis. METHODS/DESIGN: In this bi-center randomized controlled trial conducted at two tertiary referral centers in Switzerland, we plan to include 5,000 patients undergoing general, oncologic, vascular and orthopedic trauma procedures. Patients are randomized in a 1:1 ratio into two groups: one receiving surgical antimicrobial prophylaxis in the anesthesia room (75 to 30 minutes before incision) and the other receiving surgical antimicrobial prophylaxis in the operating room (less than 30 minutes before incision). We expect a significantly lower rate of surgical site infections with surgical antimicrobial prophylaxis administered more than 30 minutes before the scheduled incision. The primary outcome is the occurrence of surgical site infections during a 30-day follow-up period (one year with an implant in place). When assuming a 5% surgical site infection risk with administration of surgical antimicrobial prophylaxis in the operating room, the planned sample size has an 80% power to detect a relative risk reduction for surgical site infections of 33% when administering surgical antimicrobial prophylaxis in the anesthesia room (with a two-sided type I error of 5%). We expect the study to be completed within three years. DISCUSSION: The results of this randomized controlled trial will have an important impact on current international guidelines for infection control strategies in the hospital. Moreover, the results of this randomized controlled trial are of significant interest for patient safety and healthcare economics. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov under the identifier NCT01790529.


Assuntos
Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Projetos de Pesquisa , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Protocolos Clínicos , Esquema de Medicação , Humanos , Fatores de Risco , Infecção da Ferida Cirúrgica/microbiologia , Suíça , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento
15.
Ann Vasc Surg ; 27(8): 1173-81, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23972635

RESUMO

BACKGROUND: The objective of this study was to evaluate the effect of a 2-day international endovascular training course on the performance of trainees as compared with a control group, assessed in a bench model-based task using an objective structured evaluation protocol. METHODS: A total of 50 trainees, 28 course participants of 2 consecutive identical courses and a control group of 22 participants with a similar level of experience without course attendance, underwent baseline and final assessment (simulated arterial access task). The evaluation form consisted of a global assessment (GA), task-specific checklist percentage score (CL), and global rating scale percentage score (GR), with both percentage scores ranging from 0% (worst performance) to 100% (best performance). RESULTS: Course participants were more likely to pass the GA at final testing than the control group (odds ratio=59; 95% confidence interval [CI] 9.5-656; P<0.001). The estimated difference in percentage score at final testing between course participants and the control group was 26% (95% CI 18-34; P<0.001) for the CL and 29% (95% CI 19-40; P<0.001) for the GR. CONCLUSIONS: A 2-day structured endovascular training course significantly improves endovascular performance in a simulated environment. These results are important for the design of endovascular training curricula with the ultimate goal of contributing to patient safety.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina/métodos , Procedimentos Endovasculares/educação , Destreza Motora , Adulto , Estudos de Casos e Controles , Lista de Checagem , Currículo , Feminino , Humanos , Modelos Lineares , Masculino , Modelos Anatômicos , Modelos Cardiovasculares , Razão de Chances , Estudos Prospectivos , Inquéritos e Questionários , Análise e Desempenho de Tarefas , Fatores de Tempo
16.
Hum Gene Ther Methods ; 24(1): 28-37, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23360398

RESUMO

Therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery is an attractive approach to treat ischemia. VEGF remains localized around each producing cell in vivo, and overexpression of mouse VEGF(164) (mVEGF(164)) induces normal or aberrant angiogenesis, depending strictly on its dose in the microenvironment in vivo. However, the dose-dependent effects of the clinically relevant factor, human VEGF(165) (hVEGF(165)), are unknown. Here we exploited a highly controlled gene delivery platform, based on clonal populations of transduced myoblasts overexpressing specific VEGF levels, to rigorously compare the in vivo dose-dependent effects of hVEGF(165) and mVEGF(164) in skeletal muscle of severe combined immune deficient (SCID) mice. While low levels of both factors efficiently induced similar amounts of normal angiogenesis, only high levels of mVEGF(164) caused widespread angioma-like structures, whereas equivalent or even higher levels of hVEGF(165) induced exclusively normal and mature capillaries. Expression levels were confirmed both in vitro and in vivo by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). However, in vitro experiments showed that hVEGF(165) was significantly more effective in activating VEGF receptor signaling in human endothelial cells than mVEGF(164), while the opposite was true in murine endothelial cells. In conclusion, we found that, even though hVEGF is similarly efficient to the syngenic mVEGF in inducing angiogenesis at lower doses in a widely adopted and convenient mouse preclinical model, species-dependent differences in the relative activation of the respective receptors may specifically mask the toxic effects of high doses of the human factor.


Assuntos
Regulação da Expressão Gênica , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Células Cultivadas , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Isquemia/fisiopatologia , Isquemia/terapia , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mioblastos/citologia , Mioblastos/metabolismo , Neovascularização Patológica/metabolismo , Retroviridae/genética , Análise de Sequência de DNA , Transdução de Sinais , Especificidade da Espécie , Transdução Genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
BMJ Case Rep ; 20122012 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-23188844

RESUMO

Postoperative common carotid artery occlusion after reconstruction for type A aortic dissection can lead to major neurological morbidity. Surgical strategy to re-establish the cerebral perfusion depends on the time of onset of neurological deficits in this otherwise life-threatening disease. We present two cases with neurological deficits after replacement of the ascending aorta for a type A dissection treated with two different surgical strategies. In both cases, prompt surgical interventions improved neurological outcome.


Assuntos
Aneurisma Dissecante/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Artéria Carótida Primitiva , Dissecação da Artéria Carótida Interna/diagnóstico , Estenose das Carótidas/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Angiografia , Implante de Prótese Vascular , Artéria Carótida Primitiva/cirurgia , Dissecação da Artéria Carótida Interna/cirurgia , Estenose das Carótidas/cirurgia , Revascularização Cerebral , Ponte de Artéria Coronária , Endarterectomia das Carótidas , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Complicações Pós-Operatórias/cirurgia , Reoperação , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler em Cores , Ultrassonografia Doppler Dupla
18.
Swiss Med Wkly ; 142: w13616, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22949137

RESUMO

INTRODUCTION: Surgical site infections (SSI) are the most common hospital-acquired infections among surgical patients, with significant impact on patient morbidity and health care costs. The Basel SSI Cohort Study was performed to evaluate risk factors and validate current preventive measures for SSI. The objective of the present article was to review the main results of this study and its implications for clinical practice and future research. SUMMARY OF METHODS OF THE BASEL SSI COHORT STUDY: The prospective observational cohort study included 6,283 consecutive general surgery procedures closely monitored for evidence of SSI up to 1 year after surgery. The dataset was analysed for the influence of various potential SSI risk factors, including timing of surgical antimicrobial prophylaxis (SAP), glove perforation, anaemia, transfusion and tutorial assistance, using multiple logistic regression analyses. In addition, post hoc analyses were performed to assess the economic burden of SSI, the efficiency of the clinical SSI surveillance system, and the spectrum of SSI-causing pathogens. REVIEW OF MAIN RESULTS OF THE BASEL SSI COHORT STUDY: The overall SSI rate was 4.7% (293/6,283). While SAP was administered in most patients between 44 and 0 minutes before surgical incision, the lowest risk of SSI was recorded when the antibiotics were administered between 74 and 30 minutes before surgery. Glove perforation in the absence of SAP increased the risk of SSI (OR 2.0; CI 1.4-2.8; p <0.001). No significant association was found for anaemia, transfusion and tutorial assistance with the risk of SSI. The mean additional hospital cost in the event of SSI was CHF 19,638 (95% CI, 8,492-30,784). The surgical staff documented only 49% of in-hospital SSI; the infection control team registered the remaining 51%. Staphylococcus aureus was the most common SSI-causing pathogen (29% of all SSI with documented microbiology). No case of an antimicrobial-resistant pathogen was identified in this series. CONCLUSIONS: The Basel SSI Cohort Study suggested that SAP should be administered between 74 and 30 minutes before surgery. Due to the observational nature of these data, corroboration is planned in a randomized controlled trial, which is supported by the Swiss National Science Foundation. Routine change of gloves or double gloving is recommended in the absence of SAP. Anaemia, transfusion and tutorial assistance do not increase the risk of SSI. The substantial economic burden of in-hospital SSI has been confirmed. SSI surveillance by the surgical staff detected only half of all in-hospital SSI, which prompted the introduction of an electronic SSI surveillance system at the University Hospital of Basel and the Cantonal Hospital of Aarau. Due to the absence of multiresistant SSI-causing pathogens, the continuous use of single-shot single-drug SAP with cefuroxime (plus metronidazole in colorectal surgery) has been validated.


Assuntos
Controle de Infecções/métodos , Infecção da Ferida Cirúrgica/prevenção & controle , Anemia/complicações , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Transfusão de Sangue/estatística & dados numéricos , Cefuroxima/uso terapêutico , Estudos de Coortes , Seguimentos , Luvas Cirúrgicas , Custos Hospitalares/estatística & dados numéricos , Humanos , Controle de Infecções/estatística & dados numéricos , Modelos Logísticos , Análise Multivariada , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Fatores de Risco , Infecção da Ferida Cirúrgica/economia , Infecção da Ferida Cirúrgica/etiologia , Suíça , Fatores de Tempo
19.
J Cell Mol Med ; 16(1): 107-17, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21418520

RESUMO

We recently developed a method to control the in vivo distribution of vascular endothelial growth factor (VEGF) by high throughput Fluorescence-Activated Cell Sorting (FACS) purification of transduced progenitors such that they homogeneously express specific VEGF levels. Here we investigated the long-term safety of this method in chronic hind limb ischemia in nude rats. Primary myoblasts were transduced to co-express rat VEGF-A(164) (rVEGF) and truncated ratCD8a, the latter serving as a FACS-quantifiable surface marker. Based on the CD8 fluorescence of a reference clonal population, which expressed the desired VEGF level, cells producing similar VEGF levels were sorted from the primary population, which contained cells with very heterogeneous VEGF levels. One week after ischemia induction, 12 × 10(6) cells were implanted in the thigh muscles. Unsorted myoblasts caused angioma-like structures, whereas purified cells only induced normal capillaries that were stable after 3 months. Vessel density was doubled in engrafted areas, but only approximately 0.1% of muscle volume showed cell engraftment, explaining why no increase in total blood flow was observed. In conclusion, the use of FACS-purified myoblasts granted the cell-by-cell control of VEGF expression levels, which ensured long-term safety in a model of chronic ischemia. Based on these results, the total number of implanted cells required to achieve efficacy will need to be determined before a clinical application.


Assuntos
Separação Celular/métodos , Membro Posterior/irrigação sanguínea , Isquemia/fisiopatologia , Mioblastos/fisiologia , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Biomarcadores/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Transplante de Células , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/transplante , Ratos , Ratos Nus , Fator A de Crescimento do Endotélio Vascular/genética
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