Local activation of CB1 receptors by synthetic and endogenous cannabinoids dampens burst firing mode of reticular thalamic nucleus neurons in rats under ketamine anesthesia.

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.

Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm: Impact on Inflammation, Oxidative Stress, and Vascular Remodeling.

[Figure: see text].

Appropriateness of surgery performed for abdominal aortic aneurysm at tertiary hospitals in Spain.

BACKGROUND: The aim of this study was to analyze the appropriateness of the type of repair (open or endovascular) performed for abdominal aortic aneurysm (AAA) in five university hospitals in Spain, according to evidence-based recommendations. METHODS: A multicenter, retrospective cross-sectional study of patients with AAA who underwent elective open surgical repair (OSR) or endovascular aneurysm repair (EVAR). Data were collected on demographic and clinical variables and type of surgical repair. A pair of vascular surgeons from each participating hospital performed a blinded assessment based on GRADE recommendations. The concordance between the two evaluators and the agreement between their evidence-based recommendation and the procedure performed were assessed. RESULTS: A total of 186 patients were selected; 179 were included. Mean age was 72.5 years (standard deviation [SD], 8.4), mean Charlson Comorbidity Index (CCI) was 2.04 (SD, 1.9). OSR was performed in 53.2% (N.=99) and EVAR in 46.8% (N.=87) of cases. Overall, 65.9% (118/179) of interventions performed were considered appropriate: 50% (47/94) of OSRs and 83.5% (71/85) of EVARs. The patient characteristics were similar for all the hospitals, but the chosen surgical technique did show significant differences among these centers. There were no significant differences among the hospitals in the proportion of cases judged as appropriate, either overall (P=0.346) or for each type of procedure (P=0.531 and P=0.538 for OSR and EVAR, respectively). CONCLUSIONS: In this study, most of the AAA repairs performed were appropriate according to GRADE recommendations. A higher proportion of EVARs were considered appropriate than OSRs. Choice of AAA repair should be standardized using evidence-based clinical practice guidelines, while incorporating patient preferences, to reduce the existing variability and ensure appropriate selection of AAA repair technique.

Preoperative geriatric assessment, a promising tool to improve outcomes in aortic pathology interventions.

BACKGROUND: Due to population aging and the spread of endovascular techniques for aortic diseases, there has been an increase in older population intervened. Objectively assessing patient's global status becomes mandatory in advanced ages, as impaired functional status and frailty are associated with higher postoperative mortality rates. The aim of this paper is to evaluate the impact of a systematic geriatric preoperative assessment on the outcomes of aortic interventions. METHODS: All patients above 60 years old with surgical indication for aortic disease between September 2016 and May 2019 underwent a standardized geriatric assessment. It analyzed physiological reserve, frailty, and life expectancy. An algorithm was created for its application before intervention indication. Variables registered were patient's data, type of aortic disease, type of intervention, geriatric assessment result, mortality and follow-up time. A bivariate analysis was performed. RESULTS: One hundred forty-four patients were included. Geriatric report was unfavorable for intervention in 6.25% (N.=9). From these, 88% (N.=8) were finally rejected for intervention. In those undergoing aortic intervention (N.=127) there was a 7% mortality rate (N.=9) and in the no-intervention group (N.=17) mortality rate raised up to 35% (N.=6). No aortic-related mortality was reported. A relevant association between an unfavorable geriatric report and mortality was found "OR 0.036 (CI 0.0082-0.155)." A protective relationship between any aortic intervention and mortality was found, with OR 0.139 (CI 0.043-0.447). CONCLUSIONS: Geriatric assessment is a valid tool to estimate life expectancy and patient's physiological status. An unfavorable report correlates with short-term non-aortic mortality independently of undergoing intervention. This has a high clinical relevance, and it highlights its practical applicability to improve aortic surgery indication's quality and optimize resource investment.

Systematic review on abdominal aortic aneurysm screening cost-efficiency and methodological quality assessment.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a silent, progressive disease that can lead to death. It is easily diagnosed with noninvasive methods and its routine treatment has excellent results. This creates an optimal situation for population screening programs. The aim of this paper was to assess results and methodological quality of cost-utility studies on screening versus no screening scenarios for AAA to assess future establishment of new AAA screening programs. EVIDENCE ACQUISITON: A systematic review of efficiency (cost-effectiveness and cost-utility) studies was performed, finally selecting cost-utility studies on AAA screening versus no screening. Papers were selected that dealt with efficiency of screening for AAA according to PICOTS framework and the methodological quality assessed according to the economic evaluation analyses described by Drummond and Caro. Two independent reviewers were involved in the procedure. EVIDENCE SYNTHESIS: Research retrieved 88 studies. From those, 26 showed cost-effectiveness and cost-utility results. Finally, 10 studies had cost-utility results and suited criteria (published in the last 10 years; time-horizon: 10 years or more) for exhaustive analysis. All publications, except one, showed adequate incremental cost-utility ratios according to different national perspectives. Methodological assessment showed some quality limitations, but the majority of items analyzed were favorably answered after applying the questionnaires. CONCLUSIONS: Confirmation of the cost-utility results in this revision at a national/regional level should be the basis for the implantation of new national screening programs worldwide. The methodological evaluation applied in this revision is crucial for the corresponding future piggy-back trials to assess routine application of national AAA screening programs.

Cord blood-derived platelet concentrates as starting material for new therapeutic blood components prepared in a public cord blood bank: from product development to clinical application.

BACKGROUND: There are many advantages to using cord blood (CB) as a source of therapeutic platelet and plasma derivatives for regenerative medicine. These include availability, universal use, young donor source, and virally safe biological material, rich in tissue regenerative factors. MATERIALS AND METHODS: We aimed to validate a bioprocess design for the production of cord blood-derived platelet concentrates (CBPC) in a public Cord Blood Bank (CBB). CBPC was defined as a product of 10±5 mL, 1,000±200×109/L total platelets, free of erythrocytes and leukocytes. A total of 300 CB units were centrifuged in two steps to enrich for platelets, in compliance with Good Manufacturing Practice. The samples were tested for the degree of platelet activation present, and the levels of growth factor were analysed to evaluate their potential function. CBPC were then activated after thawing with 10% calcium gluconate to generate platelet gels (CBPG) to treat patients with diabetic foot ulcers. RESULTS: After processing, 84% of the products fulfilled the acceptance criteria. Final products contained 1,017±149×106 platelets/mL in 10±3mL of plasma. Platelet recovery was 50±9%. The methods described here ensure depletion of white and red blood cells down to a residual concentration of 0.2±0.1×106/mL and 0.03±0.02×106/mL, respectively. Platelets showed low levels of activation during processing, but were significantly activated after thawing, as indicated by an increase in CD62p expression. The growth factors EGF, VEGF, bFGF, PDGF AB/BB and TGF-ß1 were at concentrations of 1,706±123 pg/mL; 1,602±227 pg/mL; 314±26 pg/mL; 30±1.5 ng/mL; 24±2 ng/mL (mean±standard error of mean), respectively. For clinical evaluation, a total of 21 CBPG were applied in 3 patients, with no reported adverse events and improvement of ulcers in all of them. DISCUSSION: We designed and validated a highly reproducible, closed system method to manufacture high quality CBPC suitable for clinical applications using CB units not suitable for transplantation in a public CBB.

Descriptive and follow-up study of patients treated surgically for abdominal aortic aneurysm at tertiary hospitals in Spain.

BACKGROUND: The aim of this study was to assess potential variability in the clinical characteristics and treatment of patients undergoing elective surgery for abdominal aortic aneurysm (AAA) across five hospitals in Spain. METHODS: Multicenter, retrospective cohort study of patients diagnosed with AAA and treated with open surgical repair (OSR) or endovascular aneurysm repair (EVAR). We evaluated clinical and demographic variables, including comorbidity (Charlson Comorbidity Index [CCI]); anatomic characteristics; surgical risk (ASA Score); aneurysm characteristics; and in-hospital and overall mortality. All patients were followed for three years. RESULTS: A total of 186 patients were included, mean age 72.5 (standard deviation [SD], 8.4), mean CCI 2.04 (SD, 1.9). The surgical technique was EVAR in 46.8% of cases (N.=87) and OSR in 53.2% (N.=99). The in-hospital mortality rate was 2.2%, with no differences between groups. The overall mortality rate during follow-up (mean, 2.9 years) was 24.1% for EVAR versus 8.1% for the OSR group (odds ratio [OR], 3.62; 95% confidence interval [CI], 3.60-3.64; P=0.004). EVAR was the only independent risk factor for mortality (OR, 3.89; 95% CI: 3.87-3.92; P=0.004). Inter-center variability in the type of surgery was high, with EVAR accounting for 19.4% to 75% of the surgical procedures, depending on the treating center (P<0.001). CONCLUSIONS: In this study the in-hospital mortality rates for elective EVAR and OSR were similar. However, after the follow-up, patients who underwent EVAR had a three-fold greater mortality rate than those treated with OSR. There was substantial inter-hospital variability, underscoring the need to standardize treatment selection in patients who undergo elective surgery for AAA repair.

Enhanced endoplasmic reticulum and mitochondrial stress in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of cardiovascular diseases (CVDs), although their contribution to AAA development is uncertain. Therefore, we aimed to determine their implication in AAA and investigated the profile of oxysterols in plasma, specifically 7-ketocholesterol (7-KC), as an ER stress inducer.In the present study, we determined aortic ER stress activation in a large cohort of AAA patients compared with healthy donors. Higher gene expression of activating transcription factor (ATF) 6 (ATF6), IRE-1, X-binding protein 1 (XBP-1), C/EBP-homologous protein (CHOP), CRELD2 and suppressor/enhancer of Lin-12-like (SEL1L) and greater protein levels of active ATF6, active XBP1 and of the pro-apoptotic protein CHOP were detected in human aneurysmatic samples. This was accompanied by an exacerbated apoptosis, higher reactive oxygen species (ROS) production and by a reduction in mitochondrial biogenesis in the vascular wall of AAA. The quantification of oxysterols, performed by liquid chromatography-(atmospheric pressure chemical ionization (APCI))-mass spectrometry, showed that levels of 7-KC were significantly higher while those of 7α-hydroxycholesterol (HC), 24-HC and 27-HC were lower in AAA patients compared with healthy donors. Interestingly, the levels of 7-KC correlate with the expression of ER stress markers.Our results evidence an induction of ER stress in the vascular wall of AAA patients associated with an increase in circulating 7-KC levels and a reduction in mitochondrial biogenesis suggesting their implication in the pathophysiology of this disease.

Variation in the choice of elective surgical procedure for abdominal aortic aneurysm in Spain.

OBJECTIVE: The two main surgical treatments for abdominal aortic aneurysm (AAA) are open surgical repair (OSR) and endovascular aneurysm repair (EVAR). The aim of this study was to analyze variation among Spanish hospitals in the use of OSR or EVAR for AAA. A secondary aim was to assess changes in preferences for these two procedures over time. METHODS: This was a retrospective longitudinal study based on discharge data from public hospitals in Spain during 2002-2012. Patient inclusion criteria were: age >18 years, elective admission, primary diagnosis of unruptured AAA, and surgical treatment with OSR or EVAR. The characteristics of the treating center, patients, and in-hospital mortality were recorded. RESULTS: We included 16,737 patients from 114 hospitals; 6,809 (40.7%) underwent EVAR and 9,928 (59.3%) underwent OSR. The total volume of surgeries increased throughout the period, and the probability that any given procedure was EVAR increased by 20% per year (OR 1.20, P<0.001). The volume and distribution of the two procedures varied highly across the participating hospitals. Overall, in-hospital mortality rate was 3.6% and it decreased during the study period (5.3% in 2002 and 3.2% in 2012), mainly due to a decrease in OSR-related mortality, despite a slight increase in EVAR-related mortality. Hospitals with higher surgical volumes were more likely to use EVAR and have lower in-hospital mortality rates. CONCLUSION: This study reveals high variability in the surgical treatment of unruptured AAA across Spanish hospitals. The number of interventions has increased in recent years, with EVAR accounting for a growing percentage of these surgical procedures. Overall in-hospital mortality rates decreased significantly during this period, mainly due to lower mortality among patients undergoing OSR. In-hospital mortality rates were lower in higher-volume centers, regardless of the surgical approach used. Further research on variability and appropriateness of surgical management of AAA is required to assess the suitability of concentrating elective AAA repair in more experienced centers to potentially achieve better outcomes.

GRADE-Based Recommendations for Surgical Repair of Nonruptured Abdominal Aortic Aneurysm.

The objective of this study was to provide evidence-based recommendations for endovascular aneurysm repair (EVAR) versus open surgical repair (OSR) for patients with a nonruptured abdominal aortic aneurysm (AAA). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement and adhered to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Both low- and high surgical risk patients treated with EVAR showed decreased 30-day mortality, but the low-risk group had no differences in 4-year mortality. Compared with friendly anatomy, patients with hostile anatomy had an increased risk of type I endoleak. Young patients may prefer OSR. Endovascular aneurysm repair was not cost-effective in Europe. Four conditional recommendations were formulated: (1) OSR for low-risk patients up to 80 years old, (2) EVAR for low-risk patients older than 80 years, (3) EVAR for high-risk patients as long as is anatomically feasible, and (4) OSR in patients in whom it is not anatomically feasible to perform EVAR. Based on GRADE criteria, either OSR or EVAR can be suggested to patients with nonruptured AAA taking into account their surgical risk, hostile anatomy, and age. Given the weakness of the recommendations, personal preferences are determinant.

Variability of revascularization techniques among Catalan hospitals and impact on leg salvage in patients with peripheral arterial disease.

BACKGROUND: Indications for the revascularization treatment of peripheral arterial disease (PAD) generate much discussion, and practice varies significantly among hospitals. This study looked at patients with PAD admitted to all hospitals of the Catalan Health Service and analyzed patterns of revascularization techniques with subsequent amputation procedures. METHODS: We used the clinical-administrative registry of admissions of all patients in the hospitals of Catalonia, north-east Spain, between 2009 and 2014. We analyzed the clinical course of patients admitted with PAD throughout their successive hospital admissions. Variability between hospitals was described for the revascularization techniques and amputations performed. Endovascular outcomes were compared with those from open surgery. RESULTS: Annually, there were 9,828 admissions with PAD and 631 major amputations. Eight hospitals accounted for 52% of all admissions, and endovascular techniques occurred predominantly in high-tech, high-resolution or reference hospitals. The ratio of admissions involving endovascular techniques/open surgery varied from 0.02 to 3.73 according to the hospital, and had a correlation of -0.175 (P=0.447) with the percentage of performed major amputations and of 0.122 (P=0.598) ratio of minor / major amputations. At the end of the 6 studied years, endovascular revascularization resulted in lower patency and more minor amputations than open surgery, but had the same percentage of major amputations (10.3% vs. 10.7%, P=0.526) and lower in-hospital mortality (7.1% vs. 9.5%, P<0.0001). CONCLUSIONS: Interventions of PAD are centralized in complex hospitals and have an important variability depending on the treating hospital. Hospital variability in revascularization techniques seems to have no impact on leg salvage. Endovascular and surgical revascularization would result in similar percentages of major amputations.

Increased Peak Wall Stress, but Not Maximum Diameter, Is Associated with Symptomatic Abdominal Aortic Aneurysm.

OBJECTIVE: Maximum diameter (MD) is the established rupture predictor for abdominal aortic aneurysm (AAA). However, biomechanical markers from finite element analysis (FEA) could be more accurate predictors for these patients. In this study, the association between peak wall stress (PWS) and MD with symptoms of AAA was evaluated. METHODS: Patients diagnosed with infrarenal non-ruptured AAA at the centre between 2009 and 2015 were included. Clinical data, morphological variables (including MD), and the biomechanical variables PWS and diameter normalised PWS (dnPWS) in symptomatic (sAAA) and asymptomatic AAA patients (aAAA) were included. RESULTS: A total of 170 patients were analysed, 153 aAAA and 17 sAAA. MD was significantly greater in sAAA patients than in aAAA patients (70.4 mm, 95% CI 66.4-86.0 vs. 59.1 mm, 95% CI 53.7-67.8, respectively; p = .002). PWS was also significantly higher in the sAAA group (324.6 kPa, 95% CI 217.4-399.5 vs. 199.2 kPa, 95% CI 165.6-239.5; p < .01). No differences in MD were found in patients with an AAA ≥ 65 mm (43 aAAA and 14 sAAA); however, both PWS (327.4 kPa, 95% CI 239.0-473.3 vs. 229.4 kPa, 95% CI 210.0 to 289.4; p = .020) and dnPWS (4.3, 95% CI 3.17-4.67 vs. 3.03, 95% CI 2.8-3.49; p = .004) were higher in sAAA than in aAAA. CONCLUSIONS: This study suggests that MD and the biomechanical parameters obtained by finite element analysis are greater in sAAA than in aAAA. However, considering patients with MD ≥ 65 mm alone, only PWS, and particularly dnPWS, were able to differentiate sAAA from aAAA.

Pie diabético / Diabetic foot

La macroangiopatía es una complicación vascular frecuente en los pacientes diabéticos. A diferencia de la enfermedad arterial periférica (EAP) de los individuos no diabéticos, tiene una prevalencia superior y, dada la distribución distal de la afectación vascular y su asociación con la neuropatía periférica, es a menudo asintomática. Los pacientes con arteriopatía periférica y diabetes suelen tener una forma de presentación clínica más frecuente y precoz, con rápida evolución, extensa afectación y mayor número de complicaciones. Es importante diagnosticar el pie diabético, con objetivo de detectar los síntomas, prevenir la discapacidad y la pérdida de la extremidad. El diagnóstico se establece mediante la exploración clínica y la determinación del ITB con el Doppler. El tratamiento del paciente con diabetes y EAP debe ser doble: 1. modificación de los factores de riesgo vascular primarios y secundarios y 2. tratamiento de los síntomas de su arteriopatía (claudicación invalidante e isquemia crítica del miembro) y limitación de la progresión de la enfermedad

Macroangiopathy is a frequent vascular complication in diabetic patients. Unlike peripheral arterial disease (PVD) in non diabetic individuals, it has a greater prevailance and given the distal distribution of the vascular affectation and its association with peripheral neuropathy, it is often asymptomatic. Patients with peripheral arteriopathy and diabetes usually have a more frequent and precocious form of clinical presentation, with rapid evolution, extensive affectation and a greater number of complications. It is important to diagnose diabetic foot, with the objective of detecting the symptoms, preventing disability and the loss of the extremity. The diagnosis is established by means of clinical exploration and the determination of the AAI with the Doppler. The treatment of the patient with diabetes and PVD has to be double: 1. modification of primary and secondary vascular risk factors and 2. treatment of the arteriopathy symptoms (invalidating claudication and critically ischemic foot) and the limitation of the progression of the disease