Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431*) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys).

The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.

Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy.

BACKGROUND: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limbgirdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. OBJECTIVE: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. METHODS: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. RESULTS: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. CONCLUSIONS: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.

Incorporation of randomized controlled trials into organizational guidelines for obstetricians and gynecologists.

BACKGROUND: The American College of Obstetricians and Gynecologists publishes practice bulletins and committee opinions to serve as clinical guidelines for physicians. The objective of this study was to quantify the frequency that randomized controlled trials become incorporated into the American College of Obstetricians and Gynecologists documents (either practice bulletins or committee opinions). METHODS: Original research articles published in The American Journal of Obstetrics and Gynecology, The Journal of the American Medical Association, The New England Journal of Medicine, and Obstetrics and Gynecology between 2009 and 2014 were examined and randomized controlled trials (RCT) in obstetrics and gynecology were identified. Adjusted odds ratio (aOR) with 95% confidence intervals (CI) were calculated to examine the factors associated with a citable RCT being referenced versus not in ACOG documents. RESULTS: Of the 306 randomized controlled trials identified 248 (81.0%) met the inclusion criteria, with 128 (51.6%) of eligible RCT being cited The factors which increased the likelihood of a RCT being referenced, versus not being, were: if device or surgery was the intervention (aOR 3.60; 95% CI 1.85-7.00) and if the sample size of the trial was 500-999 (aOR 3.70 (1.39-9.82). The following factors were not associated with whether the RCT was or was not referenced in the ACOG documents: topic was obstetric or gynecologic, the trial was conducted in the US or abroad, multi- or single center, year of publication and the journal. CONCLUSION: Since about half of the citable randomized controlled trials published in obstetrics and gynecology are incorporated into ACOG practice bulletins and committee opinions a greater transparency is warranted as to why RCTs are or are not referenced.

Remdesivir use in pregnancy during the SARS-CoV-2 pandemic.

OBJECTIVE: To ascertain the composite maternal and neonatal outcomes in pregnant individuals with moderate, severe, or critical coronavirus disease 2019 (COVID-19) treated with remdesivir. MATERIALS AND METHODS: This is a secondary analysis of the COVID in Pregnancy Registry in Houston, Texas. Women were included if they met the criteria of moderate, severe or critical COVID-19 illness. Composite adverse maternal outcome was defined as any of the following outcomes: placental abruption, pregnancy-related hypertension, chorioamnionitis, stroke, delivery with estimated blood loss >1000 mL, diagnosis of pulmonary embolism or deep venous thromboembolism, or maternal death. Composite adverse neonatal outcome was defined as any of the following: Apgar score ≤3 at 5 min, arterial cord pH <7.0, positive SAR-CoV-2 test, intraventricular hemorrhage, periventricular leukomalacia, stillbirth, or neonatal death. Comparative analyses between participants receiving remdesivir versus those not exposed were performed. RESULTS: A total of 994 patients were diagnosed with COVID-19 infection. Of these, 95 (9.6%) met criteria for moderate, severe, or critical disease. Forty-one percent of these patients (n = 39) received remdesivir. Baseline demographic characteristics were not different between groups. No patients reported an allergic reaction with the administration of remdesivir; however, 16.7% of the patients had the medication discontinued due to transaminitis. Patients receiving the drug were more likely to have a longer illness duration on admission, more likely to require oxygen support on arrival and have a longer hospital stay. CONCLUSIONS: Remdesivir appears to be safe, well tolerated within our cohort with no cases of recorded adverse reaction.

Opioid-Free Anesthesia and Same-Day Surgery Laparoscopic Hiatal Hernia Repair.

BACKGROUND: Laparoscopic hiatal hernia repair is commonly performed with a 1 to 2 night hospitalization. Our aim was to compare the feasibility and short-term outcomes of same-day surgery (SDS) laparoscopic hiatal hernia repair with an opioid-based anesthesia protocol (OBAP) vs an opioid-free anesthesia protocol (OFAP). STUDY DESIGN: Outcomes and pharmacy costs of repairs with OBAP were compared with OFAP. Values were expressed as median (interquartile range) and costs as means. RESULTS: There were 244 primary laparoscopic repairs. OBAP was used in 191 of 244 (78.3%) vs OFAP in 53 of 244 (21.7%). The length of stay was 1 day (0 to 2) vs 0 days (0 to 1), p = 0.006. There was no difference between the percentage of patients requiring analgesics and dosage between the 2 groups. SDS was planned in 157 and performed in 74 of 122 (60.7%) vs 33 of 35 (94.3%), p < 0.001. The age was 56 years (45 to 63) vs 60 years (56 to 68), p = 0.025. There were more type I hiatal hernia in SDS-OBAP and more type III and IV in SDS-OFAP, p = 0.031. American Society of Anesthesiologists Physical Status was II (II-III) vs III (II-III), p = 0.045. SDS was not performed in 50 of 157 (31.8%), 48 of 122 (39.3%) vs 2 of 35 (5.7%), p < 0.001. Out of 157 planned SDS, nausea/retching were causes of transition in 19 of 122 (15.6%) vs 0 of 35 (0%), p = 0.020. Multivariable logistic regression showed the odds of SDS were 8.21 times (95% CI 3.10 to 21.71; p < 0.001) greater in OFAP compared with OBAP, adjusting for sex, age, body mass index, American Society of Anesthesiologists Physical Status, type of hiatal hernia, type of procedure, and duration of the operation. Patients with opioid medication after SDS discharge were 74 of 74 (100%) vs 22 of 33 (66.7%), p < 0.001. CONCLUSIONS: Opioid-free anesthesia increases the feasibility of SDS hiatal hernia repair with less perioperative nausea and comparable pain control and pharmacy cost.

Laparoscopic hiatal hernia repair as same day surgery: Feasibility, short-term outcomes and costs.

INTRODUCTION: Laparoscopic hiatal hernia repair is commonly performed with 1 night hospitalization. The aim was to assess repairs as same-day-surgery (SDS). METHODS: Costs/short-term outcomes of SDS were compared to hospital-stay < 24-h: observation (OBS) and hospital-stay ≥ 24-h: inpatient (INP). Outcomes were assessed by postoperative 30-day ER visits/readmissions. RESULTS: There were 262 procedures, excluding 50 reoperative repairs, 212 procedures were included: There were 66 SDS, 65 OBS and 81 INP. SDS vs. OBS: OBS were older, had higher ASA, less type I and more type III and IV hernias. Costs were significantly less in the SDS group with no difference in post-operative ER visits/post-discharge readmissions. SDS vs. INP: INP were older, had higher ASA, less type I and more type III and IV hernias. Costs were significantly less in the SDS group with no difference in post-operative ER visits/post-discharge readmissions. CONCLUSION: Laparoscopic hiatal hernia repair can be performed as SDS in majority of elective repairs with good short-term outcomes and reduced cost.

Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM ("familial") is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Genomic study of dilated cardiomyopathy in a group of Mexican patients using site-directed next generation sequencing.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico. METHODS: We recruited 55 unrelated DCM patients, 22 familial (F-DCM), and 33 idiopathic (I-DCM), and performed site-directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes. RESULTS: Overall diagnostic yield was 47.3%, and higher in F-DCM (63.6%) than in I-DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A-band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM-related proteins, the recent refinement ACMG/ClinGen Guidelines, and co-segregation analysis in DCM families helped increase the diagnostic yield. CONCLUSION: This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.

Let the right one in: High admission rate for low-acuity pediatric burns.

BACKGROUND: The purpose of this study was to characterize emergency pediatric burn care triage at a tertiary children's hospital to identify targets for quality improvement. METHODS: A retrospective review of patients <18 years with primary burn injuries who presented to a children's emergency department in 2016 was conducted. Demographic and injury characteristics were recorded. Low acuity was defined by size (<5% total body surface area burn), depth (not third degree), and no need for conscious sedation for debridement. Multiple logistic regression was used for analysis. RESULTS: A total of 309 pediatric burn patients were triaged in the emergency department. Patients were typically young (median 3.3 years), male (59%), Hispanic (47%), publically insured (77%), and transferred in (65%). Scalding was the most common mechanism (59%). Though most burns were small (median 2% total body surface area), not deep (

Adherence to the Pediatric Preinduction Checklist Is Improved When Parents Are Engaged in Performing the Checklist.

BACKGROUND: The World Health Organization recommends including the parents in completion of the pediatric surgical safety checklist. At our hospital, the preinduction surgical safety checklist is conducted in the preoperative holding with anesthesia, nursing, and often with the parents of children undergoing an operative procedure. We hypothesized that adherence to the preinduction checklist is better when parents are engaged in surgical safety checklist performance. METHODS: An observational study of adherence to the preinduction checklist for nonemergent pediatric operations was performed (2016-2017). Adherence was defined as verbalization of checkpoints. Only checkpoints (patient identification, procedure, site marking, weight, allergies, and NPO status) relevant to parental knowledge were evaluated. Parental engagement was based on: positive body language, eye contact, lack of distractions, and understanding of checkpoints. RESULTS: 484 preinduction surgical safety checklists were observed (interrater reliability >0.7). Partial completion occurred in 55% cases; only 41% checklists were fully completed. Parents were present for 81% of checklists, and more checkpoints were performed when parents were present (5, IQR 4-6) versus absent (2, IQR 1-3, P < .001). Increased preinduction adherence was associated with increased parent engagement by linear regression analysis (1.20, 95%CI 1.05-1.33). Staff confirmed more checkpoints with engaged parents (28-78%) versus when parents were not engaged (1-9%, P < .001 for all checkpoints). CONCLUSION: Overall preinduction surgical safety checklist performance was poor (less than half of checklists fully completed). In contrast, checklist adherence improved with parental presence and engagement during performance of the checklist.

Splanchnic vein thrombosis as a manifestation of latent myeloproliferative neoplasm associated with sticky platelet syndrome / Trombosis esplácnica como presentación de neoplasia mieloproliferativa latente asociada con síndrome de plaqueta pegajosa

Abstract Vein thrombosis of unusual sites such as the splanchnic region continues to be not only a diagnostic but also a therapeutic challenge for the clinician due to its manifestation and associated pathologies. Latent JAK2 (Janus kinase 2) positive myeloproliferative neoplasm associated with sticky platelet syndrome is unusual. We present a clinical case of a 38-year-old female patient who presented with sudden onset abdominal pain of a possible vascular origin. Splanchnic thrombosis was diagnosed in latent myeloproliferative neoplasm by identifying the JAK2V617F mutation and sticky platelet syndrome via platelet aggregometry. Off-label anticoagulation with rivaroxaban 20 mg/day was administered. During her outpatient follow-up, she did not suffer any new thrombotic episodes.

Resumen La trombosis venosa de sitios inusuales como la esplácnica continúa siendo un reto no solo diagnóstico sino también terapéutico para el clínico debido a su forma de presentación y las patologías asociadas. La neoplasia mieloproliferativa latente JAK2 (cinasa de Janus 2) positiva asociada con síndrome de plaqueta pegajosa es inusual. Se presenta un caso clínico de una paciente de 38 años de edad que debutó con dolor abdominal de inicio súbito que sugirió un posible origen vascular. Se diagnosticó trombosis esplácnica en relación con neoplasia mieloproliferativa latente por la identificación de la mutación de la JAK2V617F y síndrome de plaqueta pegajosa mediante agregometría plaquetaria. Se administró de manera off-label anticoagulación con rivaroxabán 20 mg/día. Durante su seguimiento ambulatorio no ha presentado nuevos episodios trombóticos.

Homozygous Fukutin Missense Mutation in Two Mexican Siblings with Dilated Cardiomyopathy

ABSTRACT Background: Fukuyama congenital muscular dystrophy (FCMD) is the most common form of a group of autosomal recessive disorders characterized by altered α-dystroglycan glycosylation and caused by FKTN gene mutations. However, mutations of this gene may cause a broad range of phenotypes, including Walker-Warburg syndrome, muscle-brain-eye disease, FCMD, limb-girdle muscular dystrophy without mental retardation, and cardiomyopathy with no or minimal skeletal muscle weakness. Objective: Our purpose was to describe two siblings who died at a young age with dilated cardiomyopathy (DCM), no muscle weakness, or atrophy, and were homozygous for a FKTN missense mutation. Methods: Site-directed next-generation sequencing (NGS) was performed. Pathogenicity of variants of interest was established according to the American College of Medical Genetics (ACMG) criteria, and all available first-degree relatives were screened for mutations by Sanger sequencing. Results: NGS revealed a homozygous FKTN variant in the index case (p.Gly424Ser, rs752358445), classified as likely pathogenic by ACMG criteria. Both parents and an unaffected brother were heterozygous carriers. Since the siblings had no apparent skeletal muscle weakness or central nervous system involvement, FKTN mutations were not initially suspected. Conclusions: This is the first report demonstrating that heterozygous individuals for the FKTN p.Gly424Ser mutation were healthy, while two homozygous brothers suffered severe DCM, strongly suggesting that this FKTN mutation is a rare cause of autosomal recessive DCM.

Factores de riesgo modificables del cáncer de mama: una comparación entre mujeres menores y mayores de 40 años / Modifiable risk factors for breast cancer: a comparison between women younger and older than 40 years-old

Resumen OBJETIVO: Analizar la repercusión diferencial de los principales factores de riesgo modificables asociados con el cáncer de mama en pacientes menores y mayores de 40 años. MATERIALES Y MÉTODOS: Estudio de cohorte, retrospectivo, observacional y descriptivo. Se reunió la información de las pacientes con diagnóstico o tratamiento de cáncer de mama atendidas en un centro hospitalario del Noreste de México entre enero de 2016 y diciembre de 2017. La asociación entre las distintas variables y los grupos etarios se determinó con la prueba de la χ2 de Pearson y se consideraron estadísticamente significativos los valores con p < 0.05. RESULTADOS: Se revisaron 524 expedientes clínicos de pacientes con cáncer de mama, con límites de edad entre 22 y 99 y se seleccionaron las menores de 40 años (n = 75) que representaron 14.31% del total de las pacientes atendidas, porcentaje que coincide con la prevalencia de cáncer de mama en mujeres jóvenes reportada en la bibliografía mexicana. Se encontró un efecto similar en el riesgo de padecer cáncer de mama entre ambos grupos con los siguientes factores de riesgo modificables: nuliparidad, tabaquismo, consumo de alcohol, sedentarismo y anticoncepción hormonal. La obesidad (IMC superior a 30) tuvo mayor repercusión en mujeres de más de 40 años. CONCLUSIÓN: La prevalencia de cáncer de mama en las pacientes jóvenes fue del doble de lo reportado en el ámbito internacional. Es necesario el control de peso en mujeres menores de 40 años, que permita reducir la incidencia del cáncer de mama triple negativo en esta población. Asimismo, se recomienda el control de los otros factores de riesgo modificables porque, aunque no parecen afectar significativamente a las mujeres jóvenes, su control tiene una repercusión positiva en la prevención del cáncer de mama en todos los grupos etarios.

Abstract OBJECTIVE: To analyze the differential impact of the main modifiable risk factors associated with breast cancer among patients younger than 40 years of age. MATERIALS AND METHODS: Cohort, retrospective, observational and descriptive study. The information of the patients with diagnosis or treatment of breast cancer treated in a hospital in Northeast Mexico between January 2016 and December 2017 was collected. The association between the different variables and the age groups was determined with the test of Pearson's χ2 and the values p < 0.05 were considered statistically significant. RESULTS: 524 clinical records of patients with breast cancer were reviewed, with age limits between 22 and 99 years. From this group, patients under 40 years of age (n = 75) were selected, representing 14.31% of the total number of patients treated, a percentage that coincides with the prevalence of breast cancer in young women reported in the Mexican literature. A similar impact was found on the risk of breast cancer between both groups with the following modifiable risk factors: nulliparity, smoking, alcohol consumption, sedentary lifestyle and hormonal contraception. Obesity (BMI ≥ 30) had a greater impact on women ≥ 40 years. CONCLUSION: The prevalence of breast cancer in young patients was double what was reported internationally. Weight control is necessary in women under 40 years of age, which allows reducing the incidence of triple negative breast cancer in this population. Likewise, the control of the other modifiable risk factors is recommended because, although they do not seem to significantly affect young women, their control has a positive impact on the prevention of breast cancer in all age groups.

Genes frequently associated with sudden death in primary hypertrophic cardiomyopathy / Genes frecuentemente asociados con muerte súbita en miocardiopatía hipertrófica primaria

Abstract Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy without apparent cardiac justification. Sudden cardiac death may be the first manifestation of the disease. It occurs mainly in adulthood and can be seen in childhood and adolescence where genetic origin predominates. Primary HCM (“familial”) is inherited in an autosomal dominant pattern in the 25 subtypes informed in Online Mendelian Inheritance in Man. The proteins encoded by the mutated genes are part of the sarcomere in the cardiac cells, being the thick filament the most frequently affected, with the worst prognosis. In the present article, we describe the Mendelian inheritance of the disease and the two most associated genes with sudden death: MYBPC3 and MYH7.

Resumen La miocardiopatía hipertrófica (MCH) es el aumento de grosor de la pared ventricular izquierda no relacionada con otras alteraciones cardíacas. Es una enfermedad que puede presentar como primera manifestación clínica la muerte súbita y de ahí su relevancia clínica. Aunque se presenta sobre todo en la edad adulta, puede aparecer durante la infancia y adolescencia, en las que predominan los casos de origen hereditario. La MCH primaria, de causa genética, muestra en particular un patrón de herencia autosómico dominante en los 25 subtipos reconocidos en OMIM (Online Mendelian Inheritance in Man). Las proteínas codificadas por los genes mutantes forman parte del sarcómero en células musculares cardíacas, y las variantes patogénicas de filamentos gruesos son las de mayor frecuencia y peor pronóstico. En este artículo se describen la herencia mendeliana de la enfermedad y la relación con muerte súbita de los genes más frecuentemente encontrados en ella: MYBPC3 y MYH7.

Caspase-12 activation is involved in amyloid-ß protein-induced synaptic toxicity.

Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer's disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER)-stress depending of amyloid-ß protein (Aß). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction. This synaptic damage was prevented by incubation with a wide range of caspase inhibitor, suggesting the activation of local synaptic apoptotic mechanisms. The ER-resident caspase-12 was initially identified as a mediator of Aß neurotoxicity. Thus, the current study was conducted to explore the presence and local activation of the caspase-12 in cortical and hippocampal synaptosomes isolated from rat and from the triple transgenic mouse model of AD (3xTg-AD) in the presence of Aß and ryanodine. Under these conditions, we found mitochondrial failure accompanied by a reduction in actin levels which was dependent on caspase-12 activation suggesting its participation in Aß-induced synaptic toxicity.