Development of a small animal model replicating core characteristics of takotsubo syndrome in humans
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PROVIDER: S-EPMC11227227 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:The field of mitochondrial DNA (mtDNA) replication has been experiencing incredible progress in recent years, and yet little is certain about the mechanism(s) used by animal cells to replicate this plasmid-like genome. The long-standing strand-displacement model of mammalian mtDNA replication (for which single-stranded DNA intermediates are a hallmark) has been intensively challenged by a new set of data, which suggests that replication proceeds via coupled leading- and lagging-strand synthesis (resembling bacterial genome replication) and/or via long stretches of RNA intermediates laid on the mtDNA lagging-strand (the so called RITOLS). The set of proteins required for mtDNA replication is small and includes the catalytic and accessory subunits of DNA polymerase γ, the mtDNA helicase Twinkle, the mitochondrial single-stranded DNA-binding protein, and the mitochondrial RNA polymerase (which most likely functions as the mtDNA primase). Mutations in the genes coding for the first three proteins are associated with human diseases and premature aging, justifying the research interest in the genetic, biochemical and structural properties of the mtDNA replication machinery. Here we summarize these properties and discuss the current models of mtDNA replication in animal cells.
| S-EPMC3795181 | biostudies-literature
Project description:AimsCardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies.Methods and resultsAn isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P > 0.0001). Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05).ConclusionDysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.
| S-EPMC9239582 | biostudies-literature
Project description:BackgroundDesigned in 2012 with a first implementation in 2013, NE STEM 4U is a professional development program for post-secondary students/undergraduates, and serves as a source of outreach, content knowledge generation, and STEM literacy for youth in grades kindergarten through 8th grade (ages 5-14). The model empowers post-secondary students as facilitators of inquiry-based learning within the context of an out-of-school time program. This study investigated the potential for replicating or 'franchising' this model by evaluating on the following: (1) Is the model replicable? And, if so, (2) what core elements are necessary for program fidelity? And (3) is there a dependency on a particular setting/participant type (e.g., a more rural or urban setting)?ResultsStrategic expansion of the program to different institutional types (i.e., Research 1, Research II, and a predominantly undergraduate institution), different geographical locations (i.e., rural and urban), and with various school district partners (i.e., large and small) determined that program fidelity and replicability required 4 core elements or criteria: (i) intentional programming, (ii) staff quality, (iii) effective partnerships, and (iv) program evaluation and continuous improvement. Importantly, we examined emergent themes by each site, as well as in combination (n = 16 focus group participants, n = 12 reflection surveys). These data indicated that Flexibility (21.22%), Student Engagement (i.e., Youth) (19.53%), Classroom Management (i.e., also pertaining to youth) (19.31%), and Communication (15.71%) were the themes most referenced by the post-secondary student mentors in the NE STEM 4U program, regardless of site. Finally, the YPQA results demonstrate general replication of program quality in a "franchise" location.ConclusionsThese results highlight the core elements of the NE STEM 4U program for consideration of expansion (through strategic replication or 'franchising') as a possible international model. The findings and voices highlight the program's trajectory toward success into environments that expand professional development for post-secondary students, and for delivering STEM opportunities for youth.Supplementary informationThe online version contains supplementary material available at 10.1186/s40594-021-00320-0.
| S-EPMC8795932 | biostudies-literature
Project description:ObjectiveTo establish an animal model of modified cuff tear arthropathy (mCTA) in order to better replicate the pathophysiology associated with rotator cuff tear-induced humeral head collapse.DesignmCTA was induced by transection of the rotator cuff, the long head of the biceps brachii (LHB), and superior half of the joint capsule in the right shoulder of 12-week-old rats; the left shoulder underwent sham surgery. The severity of CTA was quantitated using the Murine Shoulder Arthritis Score (MSAS). The trabecular bone of the humeral head and metaphysis was analyzed using bone histomorphometry. The expression of proinflammatory cytokines and catabolic enzymes was evaluated immunohistochemically.ResultsIn the mCTA model, the MSAS increased starting from 2 weeks after induction, and there was notable subchondral bone collapse with fibrous cells at 4 weeks. The mCTA cartilage exhibited positive staining for TNF-α, IL-1β/6, MMP-3/13, and ADAMTS5. The trabecular bone volume was reduced not only in the subchondral bone but also in the metaphysis of the humeri, and bone resorption was enhanced in these areas. In the collapsed subchondral bone, both bone formation and resorption were increased. The fibrous cells showed expression of TNF-α, IL-6, and MMP-13, along with specific markers of mesenchymal stem cells. Furthermore, the fibrous cells showed osteoblastic characteristics (RUNX2-positive) and expressed RANKL.ConclusionsThe LHB and the capsuloligamentous complex are critical stabilizers of the glenohumeral joint, serving to prevent the advancement of CTA following massive rotator cuff tears. Fibrous cells appear to play a role in the humeral head bone resorption.
| S-EPMC10407568 | biostudies-literature
Project description: Not available
| S-EPMC7276308 | biostudies-literature
Project description:Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40-41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
| S-EPMC9360576 | biostudies-literature
Project description:A healthy 66-year-old female presented to the emergency department with acute chest pain, T-wave inversion in the anterior leads, and elevated troponin-I. Coronary angiography showed a stenosis in the midportion of the left anterior descending coronary artery (LAD), which did not wrap the left ventricle (LV) apex. LV angiography demonstrated a large LV apical akinetic systolic ballooning with a 45% ejection fraction. Fractional flow reserve (FFR) of LAD lesion was 0.71. Percutaneous intervention was performed. At six months, transthoracic echocardiography was normal. Fifteen months later, the patient presented with chest pain and a small rise in troponin-I. Coronary angiogram was unchanged. Repeat FFR in distal LAD was 0.86 and left ventriculography was normal. Diagnostic criteria for Takotsubo cardiomyopathy (TTC) require the absence of obstructive coronary artery disease. In the present case, TTC was highly suspected on the basis of typical LV apex ballooning. However, significant ischemia in the same territory was demonstrated by positive FFR, which could not be falsely positive in this context. Current TTC diagnostic criteria increase specificity for diagnosing TTC. This case reminds us that it is at the price of reduced sensitivity, since there is no reason to believe that coronary lesions may protect from TTC.
| S-EPMC7060413 | biostudies-literature
Project description:Herpesviral encephalitis caused by Herpes Simplex Virus 1 (HSV-1) is one of the most devastating diseases in humans. Patients present with fever, mental status changes or seizures and when untreated, sequelae can be fatal. Herpes Simplex Encephalitis (HSE) is characterized by mainly unilateral necrotizing inflammation effacing the frontal and mesiotemporal lobes with rare involvement of the brainstem. HSV-1 is hypothesized to invade the CNS via the trigeminal or olfactory nerve, but viral tropism and the exact route of infection remain unclear. Several mouse models for HSE have been developed, but they mimic natural infection only inadequately. The porcine alphaherpesvirus Pseudorabies virus (PrV) is closely related to HSV-1 and Varicella Zoster Virus (VZV). While pigs can control productive infection, it is lethal in other susceptible animals associated with severe pruritus leading to automutilation. Here, we describe the first mutant PrV establishing productive infection in mice that the animals are able to control. After intranasal inoculation with a PrV mutant lacking tegument protein pUL21 and pUS3 kinase activity (PrV-ΔUL21/US3Δkin), nearly all mice survived despite extensive infection of the central nervous system. Neuroinvasion mainly occurred along the trigeminal pathway. Whereas trigeminal first and second order neurons and autonomic ganglia were positive early after intranasal infection, PrV-specific antigen was mainly detectable in the frontal, mesiotemporal and parietal lobes at later times, accompanied by a long lasting lymphohistiocytic meningoencephalitis. Despite this extensive infection, mice showed only mild to moderate clinical signs, developed alopecic skin lesions, or remained asymptomatic. Interestingly, most mice exhibited abnormalities in behavior and activity levels including slow movements, akinesia and stargazing. In summary, clinical signs, distribution of viral antigen and inflammatory pattern show striking analogies to human encephalitis caused by HSV-1 or VZV not observed in other animal models of disease.
| S-EPMC7145201 | biostudies-literature
Project description:BackgroundTakotsubo syndrome (TTS) is identified by its acute and transient impairment of left ventricular systolic function. Although recent research has highlighted occurrences of TTS among individuals with gastrointestinal diseases (GI diseases), comprehensive and systematic investigations focusing on this patient demographic are still scarce.MethodsThis retrospective study analyzed case reports and series that documented an association between gastrointestinal diseases (GI diseases) and Takotsubo syndrome (TTS). We conducted comprehensive searches across PubMed, Embase, and the Cochrane Database to identify relevant cases.ResultsIn patients with gastrointestinal-induced Takotsubo syndrome (GI-TTS), the primary reasons for admission were pancreatitis (15.48 %), liver failure (10.71 %), bowel obstruction (5.95 %) and liver cirrhosis (5.95 %). It is noteworthy that the main triggers for Takotsubo syndrome are surgeries related to gastrointestinal diseases (29.76 %), including liver transplantation (15.48 %) and cholecystectomy (2.38 %). Dyspnea (45.71 %) was the most common symptom, followed by abdominal pain (35.71 %) and chest pain (34.29 %). The apical type was the most frequent TTS variant (81.25 %). Compared with the All-TTS cohort, GI-TTS patients were younger, and had a lower proportion of women (69.05 % vs. 89.77 %, P < 0.001). GI-TTS patients had higher ventilation use and lower usage of β-blockers, ACEI/ARBs, aspirin, and statins, while catecholamine use was more prevalent.ConclusionsThe study underscores the potential of gastrointestinal diseases and their treatments to trigger TTS, often presenting atypical clinical features compared to TTS of all types. Given these differences, an elevated level of clinical vigilance is imperative for the timely diagnosis of TTS in patients with gastrointestinal conditions.
| S-EPMC11914903 | biostudies-literature
Project description:BackgroundTakotsubo syndrome (TTS) and spontaneous coronary artery dissection (SCAD) are now increasingly recognized. Both conditions predominantly affect females; however, the exact pathophysiology remains unclear. Large multi-center databases can help elucidate the underlying mechanism and optimize treatments to improve outcomes by allowing us to compare features and outcomes of patients with TTS and patients with SCAD.MethodsTakotsubo syndrome patients were enrolled from the International Takotsubo Registry and compared to SCAD patients from the Canadian Spontaneous Coronary Artery Dissection Cohort Study. In total 2098 TTS patients and 750 SCAD patients were included in the present study.ResultsMore than 85% of patients in both groups were females. TTS patients were older compared to SCAD patients. Physical triggers were more common in TTS patients, while emotional triggers and non-identifiable triggering events were more common in SCAD patients. Left ventricular ejection fraction was more impaired in TTS compared to SCAD. TTS patients had more major cardiovascular risk factors, while SCAD patients had a higher rate of migraines and anxiety disorders than TTS patients. Thirty-day mortality was significantly higher in TTS patients, while 30-day stroke rates were comparable between groups.ConclusionsThese findings suggest that women are at higher risk for TTS and SCAD compared to men, which should be considered in the differential diagnosis of those presenting with acute coronary syndrome. Additionally, emotional stressors play a significant role in triggering events particularly in younger women suffering from SCAD. The present findings may help clinicians better differentiate these two entities and aid in the appropriate risk stratification, diagnosis, and management.Trial registrationClinicalTrials.gov no. NCT01947621.
| S-EPMC9987537 | biostudies-literature