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4.
Eur J Med Chem ; 185: 111783, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732257

RESUMO

Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the catalytic serine residue in this enzyme. While there have been many inhibitors discovered containing a nitrile to covalently bind to the catalytic serine, we have been investigating others, particularly boronic acids and boronic esters, the latter of which have been largely unexplored as covalent warheads. Herein we report a series of computationally-designed POP boronic ester pro-drug inhibitors exhibiting nanomolar-potencies in vitro as their active boronic acid species. These easily-accessible (1-2 step syntheses) compounds could facilitate future biochemical and biological studies of this enzyme's role in neurodegenerative diseases and cancer progression.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31733353

RESUMO

CONTEXT: Lung cancer surgery is among the surgical procedures associated with the highest prevalence of pain, but prospective longitudinal studies after the pain trajectory are scarce. OBJECTIVES: We aimed to describe the pain trajectory in patients undergoing surgery for primary lung cancer and investigate whether distinct groups of patients could be identified based on different pain trajectories. METHODS: Patients (n = 264; 95% thoracotomies) provided data on the average and worst pain intensity, pain location, and comorbidities before, and at one month and five, nine, and 12 months after surgery. Pain profiles were analyzed by latent class mixed models. RESULTS: The occurrence of any pain increased from 40% before surgery to 69% after one month and decreased to 56%, 57%, and 55% at five, nine, and 12 months, respectively. Latent class mixed models identified two classes both for average and worst pain; one class started low with high ratings after one month, then returning to a level slightly higher than baseline. The other class started higher with similar scores through the trajectory. Patients reporting no pain (8%) were placed in a separate class. Higher comorbidity score, preoperative use of both pain and psychotropic medicine characterized the class with overall highest pain for average and/or worst pain. CONCLUSION: Pain was highly prevalent after surgery, and subgroups could be identified based on different pain trajectories. Patients reported both postoperative pain and pain from chronic conditions. Knowledge about vulnerable patients and risk factors for pain is important to tailor interventions and information about pain.

7.
J Med Chem ; 62(17): 7874-7884, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393718

RESUMO

Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.

8.
Perfusion ; : 267659119867005, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31446845

RESUMO

BACKGROUND: Patients with preoperative dual antiplatelet therapy prior to coronary artery bypass surgery are at risk of bleeding and blood component transfusion. We hypothesise that an optimised cardiopulmonary bypass strategy reduces postoperative blood loss and transfusions. METHODS: In total, 60 patients admitted for coronary artery bypass grafting with ticagrelor and aspirin medication withdrawn <96 hours before surgery were prospectively randomised into two equal sized groups. Cardiopulmonary bypass combined a closed Cortiva® heparin-coated circuit with low systemic heparinisation (activated clotting time < 250 seconds) and intraoperative cell salvage in the study group, whereas the control group used a Balance® coated open circuit, full systemic heparinisation (activated clotting time > 480 seconds) and conventional cardiotomy suction. This perfusion strategy was evaluated by the chest drain volume after 24 hours, perioperative haemoglobin and platelet loss accompanied by global coagulation assessments. RESULTS: Patients in the study group demonstrated significantly better outcomes signified by lower blood loss 554 ± 224 versus 1,100 ± 989 mL (p < 0.001), reduced packed red cell transfusion 7% versus 53% (p < 0.001), reduced haemoglobin -28 ± 15 versus -40 ± 14 g/L (p = 0.004) and platelet loss -35 ± 36 versus -82 ± 67 × 109/L (p = 0.001). Indices of rotational thromboelastometry indicated shorter clotting times within the internal and external pathways. Adenosine diphosphate activated platelet function was within normal range based on Multiplate® aggregometry, while ROTEM® platelet analyses indicated inhibited function both preoperatively and post-bypass. Platelet inhibition by aspirin was verified throughout the perioperative period. Platelet function showed no intergroup differences. CONCLUSION: A stringent perfusion strategy reduced blood loss and transfusions in dual antiplatelet therapy patients requiring urgent surgery.

9.
J Cardiothorac Vasc Anesth ; 33(12): 3309-3319, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31350147

RESUMO

OBJECTIVE: Investigate important clinical and operative variables associated with increases in cardiac troponin T (cTnT) as indicators of myocardial injury after coronary artery bypass grafting (CABG). DESIGN: Prospective cohort study. SETTING: Single university hospital. PARTICIPANTS: The study comprised 626 patients undergoing isolated CABG from April 2008 through April 2010 with a validation cohort (n = 686) from 2015-2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Perioperative variables were registered prospectively. The extent of diffuse coronary atherosclerosis and significant stenoses were assessed with preoperative coronary angiography. Mixed model analysis was used to construct a statistical model explaining the course of cTnT concentrations. The model was adjusted for preoperative and intraoperative/postoperative myocardial infarction (MI) for independent assessment of additional variables. Clinical factors associated with increased cTnT concentrations during and after CABG were longer duration of cardiopulmonary bypass (p < 0.001), higher preoperative creatinine (p < 0.001), New York Heart Association functional classification IV (p = 0.006), reduced LVEF (p = 0.034), higher preoperative C-reactive protein (p = 0.049), and intraoperative/postoperative MI (p < 0.001). Factors associated with decreasing cTnT concentrations during CABG were higher BSA (p < 0.001) and a recent preoperative MI (p < 0.001). The extent of diffuse coronary atherosclerosis and significant stenoses were not associated with changes in cTnT (p = 0.35). Results were similar in the validation cohort. CONCLUSIONS: Left ventricular ejection fraction, New York Heart Association classification, kidney function, inflammation status, duration of cardiopulmonary bypass, body surface area, and preoperative MI were associated with the cTnT rise-and-fall pattern related to myocardial injury after CABG. Information regarding these variables may be valuable when using cTnT in the diagnostic workup of postoperative MI.

10.
Scand Cardiovasc J ; 53(4): 220-224, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169422

RESUMO

Objectives. Two tools to categorize and present quality data, phase of care mortality analysis (POCMA) and failure to rescue (FTR) have been introduced in the cardiothoracic surgical environment, but not tested in Scandinavia. We aimed to investigate whether these tools could be used in a Norwegian patient population and to increase the understanding of why patients die after cardiac surgery. Design. A group of four, including one senior cardiothoracic surgeon and one senior anesthesiologist, scrutinized deaths within 30 days after cardiac surgery at the Clinic of Cardiothoracic Surgery, St. Olav's University Hospital, Norway between February 2012-October 2015 in line with the POCMA-methodology. We used the clinic's internal register to identify patients and utilized all available written information from each patient course. We decided whether each death was surgeon dependent, FTR or a result of a multifactorial etiology, and evaluated the strength of our decisions. Results. We identified 51 deaths out of 1983 operations in our study period, giving unadjusted mortality of 2.6%. Nine deaths were classified as surgeon dependent, 3 FTR and 39 multifactorial. Conclusions. POCMA- and FTR-analyses can be carried out in clinical data which is well documented. The operating surgeon is in many cases not responsible for operative mortality, very few die due to FTR, but most patients die due to a multifactorial etiology.


Assuntos
Procedimentos Cirúrgicos Cardíacos/mortalidade , Serviço Hospitalar de Cardiologia , Unidades de Cuidados Coronarianos , Falha da Terapia de Resgate , Mortalidade Hospitalar , Indicadores de Qualidade em Assistência à Saúde , Procedimentos Cirúrgicos Vasculares/mortalidade , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Causas de Morte , Competência Clínica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos
12.
J Thorac Cardiovasc Surg ; 156(6): 2183-2190.e2, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30319093

RESUMO

OBJECTIVES: Health-related quality of life (HRQOL) is an important end point after cardiac surgery, particularly in patients of older age. However, prospective long-term studies describing the trajectory of HRQOL after cardiac surgery are still scarce. Therefore, the aim was to assess survival, functional status, and trajectory of HRQOL 10 years after cardiac surgery. METHODS: In a prospective population-based study, 534 patients (23% aged 75 years or older, 67% male) were consecutively included before surgery. Functional status was measured according to self-assigned New York Heart Association (NYHA) classification. HRQOL was measured using the Short-Form Health Survey (SF-36). Questionnaires were given to the patients at baseline and sent by post at 6 and 12 months, and 5 and 10 years after surgery. RESULTS: Three hundred fifty-two patients were eligible after 10 years, 274 responded (77.8%). Total survival at 10 years was 67.8%. Patients aged 75 years or older at surgery had lower survival rates than younger patients (44.6% vs 74.6%, P < .001). Seven of 8 SF-36 subscales were improved at 10 years compared with baseline. Older patients improved less than younger patients and linear mixed models showed that older patients had significantly worse trajectories on 3 of 8 SF-36 subscales. NYHA classification improved from baseline to 10 years also among older patients, with 59% in NYHA class III/IV at baseline compared with 30.3% after 10 years (P < .013). CONCLUSIONS: HRQOL and function improved from before to 10 years after cardiac surgery, also for older patients. These long-term results are of major importance when discussing the use of health care resources and patient-centered clinical decision-making.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Qualidade de Vida , Sobreviventes , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Feminino , Nível de Saúde , Humanos , Estudos Longitudinais , Masculino , Saúde Mental , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Sobreviventes/psicologia , Fatores de Tempo , Resultado do Tratamento
13.
ESC Heart Fail ; 5(3): 332-342, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29431258

RESUMO

AIMS: Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. METHODS AND RESULTS: Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+ , lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (-35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (-26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function. CONCLUSIONS: Depressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid-stage of post-MI HF.


Assuntos
Cálcio/metabolismo , Insuficiência Cardíaca/etiologia , Contração Miocárdica/fisiologia , Infarto do Miocárdio/complicações , Miócitos Cardíacos/metabolismo , Biópsia , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Volume Sistólico/fisiologia
14.
Interact Cardiovasc Thorac Surg ; 27(1): 95-101, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447379

RESUMO

OBJECTIVES: During open-heart surgery, the myocardium experiences ischaemia-reperfusion injury. A single bout of moderate, 30-min exercise induces preconditioning and protects the heart from ischaemia-reperfusion injury in rats, but this has never been investigated in humans. We aimed to investigate whether 1 bout of moderate exercise 24 h prior to surgery protects against mitochondrial and cardiac damage. METHODS: Patients scheduled for elective coronary artery bypass were eligible for this pilot study. Twenty were included and randomized to the treadmill exercise group (the EX group, n = 10) 24 h preoperatively or to standard presurgical procedures (control n = 10). Right atrial (RA) and left ventricular (LV) biopsies were collected immediately before and as long as possible after aortic cross-clamping to assess the primary outcome of mitochondrial respiration by respirometry, in addition to reactive oxygen species production by fluorometry and apoptotic transcripts. Cardiac troponin T and creatine kinase myocardial brain were measured in plasma at arrival, before surgery and 6 and 24 h postoperatively. RESULTS: Mitochondrial respiration was lower in the EX group after surgery in the LV (Complex I -22%, P < 0.05 and maximal -23%, P < 0.05) and the right atrium (Complex I -25%, P < 0.05). Transcript level of the apoptosis-related marker caspase 3 was increased 1.5-fold in the LV prior to surgery in the EX group when compared with the control group, P < 0.05. Cardiac troponin T was 45% higher in the EX group than in the control group 6 h postoperatively (P = 0.03), although not significant when corrected for aortic cross-clamping time. CONCLUSIONS: Results indicate that exercise did not precondition the heart against surgery-related damage. Exercise may render the myocardium and mitochondria more vulnerable to perioperative damage. Clinical trials registration number: NCT00218985 (https://clinicaltrials.gov/ct2/show/NCT00218985).


Assuntos
Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Exercício , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Idoso , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Creatina Quinase Forma MB/sangue , Procedimentos Cirúrgicos Eletivos , Feminino , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Miocárdio/patologia , Projetos Piloto , Troponina T/sangue
17.
Eur J Cardiothorac Surg ; 53(5): 1068-1074, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29228313

RESUMO

OBJECTIVES: The aim of this study was to compare long-term mortality in patients undergoing primary isolated coronary artery bypass grafting who received ≥1 units of red blood cells (RBCs) or no RBCs. We hypothesized that a possible difference in long-term mortality was due to preoperative morbidity and/or postoperative morbidity. METHODS: This prospective cohort study, part of the Cardiac Surgery Outcome Study (CaSOS) at St. Olavs University Hospital, Trondheim, Norway, included patients operated on from 2000 through 2014 (n = 4014) and excluded those with large intra- or postoperative blood loss or 30-day mortality. Observed mortality from 30 days to 15 years postoperatively was compared between patients who received RBC transfusion and those who did not. Cox regression analysis was performed with unadjusted models, adjusting for pre- and intraoperative covariates, and with further adjustment for postoperative complications. Sensitivity analyses were performed with propensity score matching or including 30-day mortality. RESULTS: The unadjusted hazard ratio (HR) for long-term mortality was 2.10 (1.81-2.43; P < 0.01) for transfused patients. After adjusting for pre- and intraoperative variables, the HR was 1.26 (1.04-1.53; P = 0.02). With further adjustment for postoperative complications, RBC transfusion was no longer significant and the HR was 1.19 (0.98-1.44; P = 0.08). These results were supported by the sensitivity analyses. CONCLUSIONS: The study indicated that most of the association between RBC transfusion and long-term mortality following primary isolated coronary artery bypass grafting was due to confounders, especially from postoperative complications.


Assuntos
Ponte de Artéria Coronária/mortalidade , Ponte de Artéria Coronária/métodos , Transfusão de Eritrócitos/mortalidade , Complicações Pós-Operatórias/mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
18.
Eur Heart J Case Rep ; 2(4): yty113, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31020189

RESUMO

Background: Chylothorax is a rare clinical condition that results from thoracic duct damage with leakage of chyle from the lymphatic system to the pleural space. Rarely, constrictive pericarditis has been associated with chylothorax, but to our knowledge only in relation to secondary causes such as tuberculosis, HIV, or malignancy. Case summary: A previously healthy 63-year-old man presented with effusive-constrictive pericarditis, recurrent right-sided pleural effusion, and chylothorax. There was no history of co-morbidities, surgical illness, or cardiac procedures. No single aetiologic factor was identified despite comprehensive assessment. Substantial immunosuppressive therapy was given without a sufficient clinical response. Pericardiectomy resulted in resolution of the constrictive haemodynamics and terminated chylous effusion. Discussion: The hypothesized mechanisms for development of chylothorax in association with constrictive pericarditis are the increased effective capillary infiltration secondary to central venous hypertension and reduced lymphatic drainage due to high pressure in the left subclavian vein. Increased capillary filtration may result in excessive lymph formation. However, the mechanism is not completely understood.

19.
Scand J Trauma Resusc Emerg Med ; 25(1): 73, 2017 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-28716150

RESUMO

BACKGROUND: Accidental hypothermia with cardiac arrest represents a challenge for pre-hospital rescuers as well as in-hospital staff. For pre-hospital personnel, the main focus is to get the patient to the correct destination without unnecessary delay. For in-hospital personnel early information is vital to assess the possibility for resuscitation with extracorporeal re-warming. The challenge is augmented when rescuers must cross national borders to reach and/or deliver the patients. We present a case where three adolescent boys suffered severe hypothermia after a canoeing accident in Sweden. CASE PRESENTATION: Three 14-year-old boys were canoeing a mountain lake close to the Norwegian border when their boat capsized and they all fell into the cold water. The rescue operation was hampered by rough weather conditions, and immersion times spanned from 63 to 125 min. Flight times from the scene of accident to the nearest ECMO center in Norway (Trondheim) and Sweden (Umeå) were about 30 and 90 min respectively. Two of the victims showed no vital signs after retrieval from the water and had extremely low body temperatures. They were brought to Trondheim University Hospital where they were resuscitated successfully with extracorporeal re-warming. Unable to be weaned from ECMO in the initial phase, both patients were retrieved by mobile ECMO teams to Karolinska University Hospital, from where they were discharged to their homes with good outcomes, although with some sequelae. A third victim with moderate to severe hypothermia without cardiac arrest was treated at a local hospital, from where he after a short stay was discharged without physical sequelae. CONCLUSION: These cases are a reminder of the traditional mantra that «no one is dead until warm and dead¼. Good communication between pre- and in-hospital staff can be vital for optimizing patient treatment when handling victims of severe hypothermia, and especially when there is multiple victims. Communication between neighboring countries, but even neighboring regions within the same country, can be challenging. We encourage regions similar to ours to review protocols regarding hypothermia management, making them more robust before incidents like this take place.


Assuntos
Parada Cardíaca/terapia , Hipotermia/terapia , Acidentes , Adolescente , Comunicação , Oxigenação por Membrana Extracorpórea , Humanos , Masculino , Noruega , Ressuscitação , Reaquecimento , Suécia , Transporte de Pacientes
20.
Ann Thorac Surg ; 104(4): 1313-1317, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28648540

RESUMO

BACKGROUND: Less-than-optimal long-term patency of the saphenous vein is one of the main obstacles for the success of coronary artery bypass grafting (CABG). Results from the IMPROVE-CABG trial has shown that harvesting the saphenous vein with a pedicle of perivascular tissue less than 5 mm while using manual distention provides comparable occlusion rates but significantly less intimal hyperplasia at early follow-up. The impact of pedicled veins on duration of operations, leg wound infections, and postoperative bleeding is unknown. METHODS: One hundred patients undergoing first-time elective CABG were randomly assigned to conventional or pedicled vein harvesting. Perioperative and postoperative data were collected prospectively during the hospital stay and at follow-up. RESULTS: Duration of extracorporeal circulation was significantly longer in the pedicled vein group (mean: 76 min versus 65 min, p = 0.006); however, no significant difference was found in the cross-clamp time. No significant difference was found in intraoperative vein graft flow, postoperative bleeding, or leg wound infections (4% in each group). No reoperations were due to vein graft bleeding. CONCLUSIONS: Harvesting a pedicled vein provides comparable postoperative bleeding and leg wound infection rates in selected patients. The technique is associated with a slightly longer duration of extracorporeal circulation than harvesting conventional veins. Promising early results using the pedicled vein technique may contribute to a change in standard vein harvesting technique for CABG in selected patients.


Assuntos
Ponte de Artéria Coronária/métodos , Veia Safena/transplante , Idoso , Ponte de Artéria Coronária/efeitos adversos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Infecção da Ferida Cirúrgica/etiologia , Coleta de Tecidos e Órgãos/métodos , Transplante Autólogo , Grau de Desobstrução Vascular
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