Estudio mediante modelado y simulación del efecto de los fármacos y las mutaciones en la regulación intracelular del calcio en cardiomiocitos ventriculares de perro

[ES] En el presente TFG se pretende estudiar, mediante simulación computacional, el efecto de diferentes fármacos y mutaciones en la regulación de la concentración intracelular de calcio en células cardiacas ventriculares. Puesto que muchos de estos experimentos se desarrollan habitualmente utilizando corazones caninos, el estudio se centrará en cardiomiocitos de perro. Para realizar el estudio, se desarrollará un programa informático capaz de simular el potencial de acción, las corrientes iónicas y las concentraciones iónicas en el tipo de células mencionadas. El programa se desarrollará en entorno Matlab, y deberá incluir una interfaz gráfica de usuario y un motor de cálculo. El efecto de los fármacos y las mutaciones se modelará mediante factores multiplicativos de las conductancias máximas de los canales iónicos afectados por el fármaco o la mutación. Se llevará a cabo un estudio de sensibilidad para determinar la influencia relativa de cada fármaco/mutación en los parámetros que caracterizan los transitorios de calcio intracelular que determinan la contracción celular, tales como los valores diastólicos y sistólicos o la constante de tiempo de decaimiento, entre otros.Renú Carretero, E. (2017). Estudio mediante modelado y simulación del efecto de los fármacos y las mutaciones en la regulación intracelular del calcio en cardiomiocitos ventriculares de perro. http://hdl.handle.net/10251/86987.TFG

Bloqueo de la articulación metacarpofalángica por osteofito de la cabeza del metacarpiano

Se presenta el caso de una paciente de 79 años de edad que acudió al Servicio de Urgencias de nuestro centro con un bloqueo de la articulación metacarpofalángica (MF) del dedo medio ocasionado por un osteofito en la cara cubital de la cabeza del tercer metacarpiano. El estudio radiológico permitió observar la presencia del osteofito y su extirpación permitió recuperar la normal excursión del ligamento colateral cubital de la art. MF y la extensión completa de la articulación.A 79 years old woman that presented her middle finger metacarpophalangeal joint blocked in flexion because and osteophite on the dorsal-ulnar aspect of the head of the metacarpal is presented. Diagnostic was stablished after radiological study. Resection of the osteophite allowed the ulnar collateral ligament come back to its normal excursion and complete extension of the joint was regained

Prognostic significance of infarct size and location: The case of insular stroke

The prognostic relevance of strokes in different locations is debated. For example, insular strokes have been associated with increased mortality, but this association could reflect their greater severity. In two independent cohorts of patients with supratentorial ischemic stroke (n = 90 and 105), we studied the prognostic consequences of lesion size and location using voxel-based lesion-symptom mapping before and after volume control, which better accounts for total lesion volume. Strokes affecting the insula were larger than non-insular strokes (28 vs 2cc and 25 vs 3cc, p < 0.001 in both cohorts). A number of supratentorial areas (mainly in the left hemisphere), including the insula, were associated with poor functional outcome in both cohorts before (4014 voxels) and after volume control (1378 voxels), while the associations with death were greatly reduced after volume control (from 8716 to 325 voxels). Exploratory analyses suggested that the method of lesion volume quantification, the National Institutes of Health Stroke Scale hemispheric bias and patient selection can result in false associations between specific brain lesions and outcomes. In conclusion, death in the first months after stroke is mainly explained by large infarct volumes, whereas lesions of specific supratentorial structures, mostly in the left hemisphere, also contribute to poor functional outcomes

Elevated glucose is associated with hemorrhagic transformation after mechanical thrombectomy in acute ischemic stroke patients with severe pretreatment hypoperfusion

Several pretreatment variables such as elevated glucose and hypoperfusion severity are related to brain hemorrhage after endovascular treatment of acute stroke. We evaluated whether elevated glucose and severe hypoperfusion have synergistic effects in the promotion of parenchymal hemorrhage (PH) after mechanical thrombectomy (MT). We included 258 patients MT-treated who had a pretreatment computed tomography perfusion (CTP) and a post-treatment follow-up MRI. Severe hypoperfusion was defined as regions with cerebral blood volume (CBV) values < 2.5% of normal brain [very-low CBV (VLCBV)-regions]. Median baseline glucose levels were 119 (IQR = 105-141) mg/dL. Thirty-nine (15%) patients had pretreatment VLCBV-regions, and 42 (16%) developed a PH after MT. In adjusted models, pretreatment glucose levels interacted significantly with VLCBV on the prediction of PH (p-interaction = 0.011). In patients with VLCBV-regions, higher glucose was significantly associated with PH (adjusted-OR = 3.15; 95% CI = 1.08-9.19, p = 0.036), whereas this association was not significant in patients without VLCBV-regions. CBV values measured at pretreatment CTP in coregistered regions that developed PH or infarct at follow-up were not correlated with pretreatment glucose levels, thus suggesting the existence of alternative deleterious mechanisms other than direct glucose-driven hemodynamic impairments. Overall, these results suggest that both severe hypoperfusion and glucose levels should be considered in the evaluation of adjunctive neuroprotective strategies

Endovascular treatment improves cognition after stroke. A secondary analysis of REVASCAT trial

Objective: To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial. Methods: REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded. Results: From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51-6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60-8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life. Conclusions: Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery. Classification of evidence: This study provides Class I evidence that for patients with stroke from acute anterior circulation proximal arterial occlusion, thrombectomy improves performance on the TMT at 3 months

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, setting, and participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main outcomes and measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40

Effectiveness of Thrombectomy in Stroke According to Baseline Prognostic Factors: Inverse Probability of Treatment Weighting Analysis of a Population-Based Registry

Background and Purpose In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors. Methods Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score 85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score 3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups' criteria). Results Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3). Conclusions Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors

Glucose modifies the effect of endovascular thrombectomy in patients with acute stroke: a pooled-data meta-analysis

Background and Purpose: Hyperglycemia is a negative prognostic factor following acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy in patients with large vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of endovascular thrombectomy in acute stroke. Methods: Seven randomized trials compared endovascular thrombectomy with standard care between 2010 and 2017 (HERMES Collaboration). 1764 patients with large vessel stroke were allocated to endovascular thrombectomy (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome [modified Rankin Scale (mRS) range: 0-6; lower scores indicating less disability] at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results: Median (IQR) serum glucose on admission was 120 (104-140) mg/dl [6.6mmol/l (5.7-7.7) mmol/l]. Endovascular thrombectomy (EVT) was better than standard care in the overall pooled-data analysis [common odds ratio (acOR), 2.00 (95% CI 1.69–2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose &lt; or &gt; 90mg/dl (5.0mmol/l) [(p=0.019 for interaction, acOR 3.81 (95% CI 1.73–8.41) for patients &lt; 90 mg/dl vs 1.83 (95% CI 1.53–2.19) for patients &gt; 90 mg/dl], and glucose &lt; or &gt; 100mg/dl (5.5mmol/l) [(p=0.004 for interaction, acOR 3.17 (95% CI 2.04–4.93) vs acOR 1.72 (95% CI 1.42–2.08)], but not between subgroups above these levels of glucose. Conclusions: Endovascular thrombectomy improved stroke outcomes compared to standard treatment regardless of glucose levels but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100mg/dl (5.0-5.5mmol/l). Whether tight control of glucose improves the efficacy of endovascular thrombectomy following large vessel stroke warrants appropriate testing

Effectiveness of thrombectomy in stroke according to baseline prognostic factors: inverse probability of treatment weighting analysis of a population-based registry

Background and Purpose In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors. Methods Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score ≤2) and survival at 3 months was studied using inverse probability of treatment weighting (IPTW) analysis in three pre-defined baseline prognostic groups: poor (if pre-stroke disability, age >85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score 3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups’ criteria). Results Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3). Conclusions Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors