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Intraoperative patient movement under general anesthesia, even with multiple monitoring modalities and adequate anesthetic depth, is rare but can lead to serious complications. Such movements are particularly dangerous in neurosurgical procedures, where precision is crucial. Similar risks exist in ophthalmic, spinal, and cardiac surgeries, where patient immobilization is vital to prevent adverse outcomes. This report examines the case of a 37-year-old male diagnosed with recurrent cholesterol granuloma located at the petrous apex, which necessitated neurosurgical intervention. During the procedure, the patient was placed under deep general anesthesia, and multiple neuromonitoring techniques were used to track neural and motor activity. Despite maintaining stable hemodynamic parameters and unremarkable neuromonitoring results, the patient suddenly exhibited abrupt, forceful movements involving his head and upper arms. This unexpected event during a delicate neurosurgical procedure posed a significant challenge, prompting a deeper investigation into the possible underlying causes of the patient's sudden movements, which could include factors such as insufficient anesthetic depth, muscular or neural irritation, seizure activity, or mechanical factors related to surgical equipment or technique. This case highlights the critical role of comprehensive intraoperative monitoring in ensuring patient safety, particularly during complex neurosurgical procedures where precision is essential. The use of total intravenous anesthesia (TIVA), as was used in this case, presents unique challenges, as it requires a careful balance of maintaining adequate anesthetic depth without interfering with the neuromonitoring signals used during the procedure to ensure neural integrity.
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Apexification procedure on a necrotic, infected tooth with an open apex is achievable if the canal is adequately disinfected. This case report aims to add an endodontic case to the body of knowledge currently available on the application of concentrated growth factor (CGF). A 24-year-old man with a history of a fall 15 years earlier developed apical periodontitis and pulpal necrosis in his maxillary central incisor with an open apex. Following the preparation of the access cavity, a solution containing 20 mL of sodium hypochlorite solution (5.25%) and 10 mL of 0.2% chlorhexidine was used to irrigate the canal successfully, and paper points were used to dry it. The canal was covered with a calcium hydroxide dressing for 10 days. The patient's right antecubital vein yielded 10 mL of whole blood, from which CGF was made. After the removal of the intracanal dressing, the CGF was placed into the canal to act as apical matrix to stabilize the mineral trioxide aggregate. The canal underwent composite restoration after being obturated. One year later, the clinical examination showed that the tests for palpation and percussion were negative. Both the electric and cold pulp tests yielded positive results for the tooth. Regression of the periapical lesion was seen on radiographic evaluation. Our case report's findings lead us to the conclusion that, in certain circumstances, complete canal disinfection can be used to treat necrotic, infected immature teeth, and that CGF might make an excellent scaffold matrix for treating open apex cases.
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Ulcerative colitis (UC) can lead to the generation of large amounts of reactive oxygen species and DNA damage. DNA repair caused by base excision repair (BER) enzymes is an important mechanism for maintaining genomic integrity. However, the specific relationship between the function of BER enzymes and UC remains unclear. To address this, we conducted a study on non-cancerous colon tissue from patients with UC, focusing on the role of apurinic/apyrimidinic endonuclease 1 (APEX1) in BER to explore its significance in the progression of UC. Our research found that the expression of APEX1 in epithelium cells was significantly correlated to the severity of inflammatory bowel disease (IBD) and the infiltration and function of neutrophils in human UC and mouse models, particularly in relation to neutrophil extracellular traps (NETs) and the degranulation processes. APEX1 deficiency resulted in decreased production of the chemokines CXCL1 by the NF-κB pathway in epithelium cells, leading to reduced accumulation and activation of neutrophils associated with colitis in colon tissue, as well as decreased levels of IL-1ß. Furthermore, APEX1 deficiency reduced symptoms of colitis by decreasing epithelial cell apoptosis and altering the gut microbiome. Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function.
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The petrous apex is medial most part of temporal bone, which is surrounded by vital structures. Cholesterol granuloma is the most common benign lesion of the petrous apex. Symptoms are related to mass effect and/or direct involvement of closely adjacent vital structures. The lesions can be manged either by open surgery via craniotomy or through the newer endoscopic approach. Case report and review of the literature concerning cholesterol granulomas of the petrous apex and their management. The lesion was approached endoscopically trans nasal and trans sphenoid and cholesterol granuloma was excised and marsupialised. Post operative patient recovery was uneventful. Endonasal Endoscopic approach has significantly lower complication rate when compared to open approaches. Petrous apex lesions are rare and need a multidisciplinary team approach for optimal management. By endoscopic approach one can remove lesion or marsupialize the sac with natural drainage into sinus and result in better prognosis and minimal chance of recurrence. Endonasal procedure has also lower complication rates and shorter median follow-up than open approaches.
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Coronary arteries are typically identified based on the myocardial territory they supply. In rare cases of coronary artery anomalies, the apex of the heart may be supplied by arteries other than the left anterior descending artery. While it is more common for the posterior descending artery from the right coronary artery to supply the apex, there are rare instances where the left circumflex (LCX) artery performs this function. This case report describes an unusual occurrence where the left ventricular apex is supplied by an obtuse marginal branch of the LCX artery. We present this case due to its rarity, unique presentation, and the challenges it poses for both medical and surgical management.
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Background: Accurate determination of the working length (WL) is crucial for successful endodontic treatment. Various methods, including radiography and electronic apex locators (EALs), are employed for WL measurement, each with its advantages and limitations. Aim: This study aimed to compare the accuracy of WL determination using conventional radiography and the Root ZX Mini EAL against an ex vivo gold standard method. Materials and Methods: Fifty single-rooted teeth scheduled for extraction were included. WLs were determined using radiography (Grossman's method) and the Root ZX Mini EAL. An ex vivo method served as the gold standard with WL carried out on extracted teeth under a stereomicroscope. Statistical analysis included Paired samples t-test, Chi-square test, and Bland-Altman plots. Results: The mean WL values were comparable among methods, with slight variations in precision. The Root ZX Mini EAL demonstrated significantly lower mean absolute error compared to radiography (P < 0.001). Accuracy within ± 0.5 mm and ± 1 mm tolerance ranges favored the EAL over radiography (P = 0.04 and P = 0.004, respectively). Conclusion: The Root ZX Mini EAL exhibited superior accuracy and lower error rates in WL determination compared to radiography. Integrating EALs alongside radiographic techniques is recommended to optimize WL precision in clinical practice.
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Orbital apex syndrome (OAS) is a complex condition characterized by visual loss, diplopia, and eye pain that occurs secondary to several pathological processes involving the orbital apex. We report a case of acute invasive fungal rhinosinusitis (AIFRS) associated with OAS. A 76-year-old man with left-sided visual loss, diplopia, palpebral ptosis, and headache was diagnosed with OAS secondary to Tolosa-Hunt syndrome and received systemic corticosteroid therapy from his neurologist. Owing to persistent symptoms, we opened the optic canal using a transnasal endoscopic approach for a surgical biopsy of the orbital apex lesions. Histopathological evaluation revealed numerous Aspergillus organisms in the biopsied granuloma. After surgical debridement, he received a 12-month course of voriconazole, and no recurrence of AIFRS occurred during 8-year follow-up. Patients with OAS may occasionally be prescribed corticosteroids because the clinical manifestations of AIFRS-induced OAS are similar to those observed in OAS secondary to Tolosa-Hunt syndrome, especially no nasal symptoms which is known to respond to corticosteroid therapy. Because both AIFRS-induced OAS and OAS secondary to Tolosa-Hunt syndrome induce ophthalmoplegia, proptosis, eye pain, it is sometimes difficult to differentiate these two diseases in early stage. However, corticosteroid therapy causes exacerbation of fungal infection in patients with AIFRS-induced OAS resulting in delayed accurate diagnosis and poor prognosis. AIFRS is associated with a high mortality rate ; therefore, transnasal endoscopic biopsy of orbital apex lesions before corticosteroid administration is recommended in patients with OAS. J. Med. Invest. 71 : 310-313, August, 2024.
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Rinite , Sinusite , Humanos , Masculino , Idoso , Sinusite/complicações , Sinusite/patologia , Sinusite/microbiologia , Rinite/patologia , Rinite/microbiologia , Rinite/complicações , Biópsia , Síndrome de Tolosa-Hunt/diagnóstico , Síndrome de Tolosa-Hunt/patologia , Endoscopia , Doenças Orbitárias/patologia , Doenças Orbitárias/microbiologia , Doenças Orbitárias/etiologia , Doença Aguda , Síndrome , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , RinossinusiteRESUMO
The two basic approaches to elucidating how life began both date from Darwin. The first, that of the experimentalists, stems from Darwin's famous "warm little pond" letter to Joseph Hooker of 1871. This approach, an attempt to replicate the sequential events leading to life's origin, is exemplified by the "primordial soup" hypothesis of A.I. Oparin (1924) and J.B.S. Haldane (1929); the Miller-Urey laboratory synthesis of amino acids under possible primitive Earth conditions (1953); and Joan Oró's nonbiological synthesis of the nucleic acid adenine (1959). The second approach, that of the observationalists who search for relevant evidence in the geological record, dates from Darwin's 1859 On the Origin of Species, in which he laments the "inexplicable" absence of a pre-Cambrian fossil record. Darwin's concern spurred a century of search that was ultimately rewarded by Stanley Tyler's 1953 discovery of diverse microscopic fossils in the ~1900 Ma Gunflint Chert of southern Canada. Tyler's find was soon followed by a cascade of discoveries worldwide; the establishment of a new field of science, Precambrian paleobiology; and, more recently, the discovery of 3400 and ~3465 Ma Paleoarchean microfossils, establishing that primordial life evolved early, far, and fast. Though progress has been made, much remains to be learned in the foci of this Origin of Life 2024 volume, for which this essay is the history-reviewing "stage setter".
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Orbital tuberculosis is a rare form of extra pulmonary TB and may arise either by hematogenous route or spread directly from the paranasal sinus. We herein report two cases of orbital TB with a vision threatening complication. Case-1 is a 31-year-old female with a headache, a diminution of vision in the right eye, and pain in ocular movement. On examination, there was no proptosis with RAPD present in right eye and tenderness on palpation. CEMRI revealed a diffuse infiltrating lesion at the orbital apex, suggesting of inflammatory pathology. Case-2 is a 40-year-old male with similar complaints in the left eye, CECT showed edema and swelling in the optic nerve and extraocular muscle of the left eye. A detailed investigation was done, and a diagnosis of orbital tuberculosis was made in both patients. They were started on ATT and oral steroids but lost follow-up initially and due to delayed treatment, it led to irreversible vision loss. A long-term follow-up showed resolution of ocular symptoms with occasional headaches.
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It never rains in standard lab-confinements; thus we have limited understanding of animal reactions to water and wetness. To address this issue, we sprayed water on different body parts of rats and measured drying and fur temperature by thermal imaging while manipulating behavior, sensory cues and fur. Spraying water on rats resulted in fur changes (hair clumping, apex formation), grooming, shaking, and scratching. Anesthesia abolished behavioral responses, interfered with fur changes, and slowed drying. Spraying water on different body parts resulted in differential behavioral drying responses. Spraying the head resulted in grooming and shaking responses; water evaporated from the head twice as fast as water sprayed on the animal's back or belly. We observed no effect of whisker removal on post-water-spraying behavior. In contrast, local anesthesia of dorsal facial skin reduced post-water-spraying behavioral responses. Shaving of head fur drastically enhanced post-water-spraying behaviors, but reduced water loss during drying; indicating that fur promotes evaporation, acting in tandem with behavior to mediate drying. Excised wet fur patches dried and cooled faster than shaved excised wet skin. Water was sucked into distal hair tips, where it evaporated. We propose the wet-fur-heat-pump-hypothesis; fur might extract heat required for drying by cooling ambient air.
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Comportamento Animal , Sinais (Psicologia) , Animais , Ratos , Comportamento Animal/fisiologia , Masculino , Água , Pelo Animal , Asseio Animal/fisiologia , Dessecação/métodos , Ratos Sprague-Dawley , MolhabilidadeRESUMO
Orbital foreign bodies, especially organic materials, can cause severe eye and orbital damage. Orbital apex syndrome (OAS), a complex condition affecting multiple cranial nerves, is often caused by trauma, among other factors. The patient was a three-year-old boy who fell onto a tree stump three days prior. He presented to the emergency department with left-sided eyelid edema, ptosis, traumatic mydriasis, numbness, and ophthalmoplegia and was diagnosed with OAS. Despite treatment with intravenous methylprednisolone, analgesia, and antibiotics, his condition did not improve after the transnasal endoscopic removal of the foreign body. This case highlights OAS caused by a wooden orbital foreign body requiring prompt, multidisciplinary surgical intervention. Early diagnosis and prompt intervention are crucial to preventing devastating outcomes like OAS and permanent visual impairment. Given the limited understanding of this condition, further research is essential to optimize management strategies and improve patient outcomes.
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Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1, APEX1, REF1, HAP1) is an abasic site-specific endonuclease holding critical roles in numerous biological functions including base excision repair, the DNA damage response, redox regulation of transcription factors, RNA processing, and gene regulation. Pathologically, APE1 expression and function is linked with numerous human diseases including cancer, highlighting the importance of sensitive and quantitative assays to measure APE1 activity. Here, we summarize biochemical and biological roles for APE1 and expand on the discovery of APE1 inhibitors. Finally, we highlight the development of assays to monitor APE1 activity, detailing a recently improved and stabilized DNA Repair Molecular Beacon assay to analyze APE1 activity. The assay is amenable to analysis of purified protein, to measure changes in APE1 activity in cell lysates, to monitor human patient samples for defects in APE1 function, or the cellular and biochemical response to APE1 inhibitors.
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Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Ensaios Enzimáticos , Inibidores Enzimáticos , Humanos , Dano ao DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , Ensaios Enzimáticos/métodos , Inibidores Enzimáticos/farmacologiaRESUMO
Chloroform is among the most common solvents for root canal treatment. Despite its classification as a potential carcinogen, it is effective if used correctly. Inappropriate use can lead to severe complications, including persistent pain, gingival recession, and necessitating surgical intervention to resect necrotizing bone.
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Aim and background: The management of avulsed immature teeth poses a significant challenge to clinicians, as prolonged dry time before reimplantation may lead to replacement resorption or ankylosis. Case description: Recent studies have shown promising results with the use of an intracanal proprietary pharmaceutical preparation, followed by sealing of the orifice with mineral trioxide aggregate (MTA). Angiography suggested the presence of vascularized tissue after 1 year, indicating successful regeneration of pulpal tissue in the radicular area. Conclusion: Despite an unfavorable crown-root fracture leading to tooth extraction after 9 months, histological examination revealed regular root dentin formation, indicating a favorable outcome. Clinical significance: These findings offer hope for the management of avulsed immature teeth and underscore the importance of early intervention and appropriate treatment selection. How to cite this article: Rathi N, Agrawal A, Thosar N, et al. Regeneration of Pulp and Radicular Tissues in a Nonvital Avulsed Tooth with Open Apex: A Case Report. Int J Clin Pediatr Dent 2024;17(5):596-600.
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Purpose: Lateral hinge fracture is a significant complication of medial opening wedge high tibial osteotomy. While fracture risk is closely associated with the osteotomy apex position, the optimum position remains variable within the literature. Our hypothesis is that stresses at the osteotomy apex predicted by finite element analysis can be used to identify an apex position which minimises intra and postoperative fracture risks. Methods: A finite element model was studied to investigate the effect of varying the hinge position on fracture risk and severity for a given bone geometry; variables analysed included stress, strain and micromotion levels. Nine further knee models were studied to assess the variability between patients' bone properties and examine the effect of apex location on strains. Results: Lateral hinge width and height significantly influence intra-operative stress, strain, and fracture risk, while hinge width predominately determines postoperative stability. Wider hinges improve postoperative stability, but increase the likelihood of intra-articular fractures. Aiming the apex at the fibular head height minimises strain. The osteotomy apex should be located such that the hinge width is equal to 13% of the medial-lateral width to minimise apex stress and fracture risk while preserving sufficient bone at the hinge for stability. The height of the apex from the tibial plateau should maintain a minimum value of 16% of the medial-lateral width to avoid intra-articular fracture, with the apex below the fibula head if necessary. The size of the tibia does not alter the optimal location, making our findings applicable across all tibia sizes. Conclusions: Our study has investigated and verified a proposed optimal apex position, based upon fracture risk prediction and micromotion at the osteotomy apex. This is clinically useful due to the potential use of the apex point on preoperative 2D radiographs when planning surgery. Level of Evidence: Not applicable.
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It was reported that serum apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) level was higher in acute myocardial infarction (AMI) patients than in angina. This study aimed to investigate the role and mechanism of APEX1 in AMI progression. The mRNA and protein levels of APEX1 and zinc finger CCHC domain containing 9 (ZCCHC9) in blood specimens of AMI patients and normal controls were determined by RT-qPCR and Western blot assays, respectively. H9c2 cardiomyocytes were treated with angiotensin II (Ang II) to induce cardiomyocyte injury and then transfected with small interfering RNA against APEX1 (si-APEX1) or overexpression plasmids of ZCCHC9 (pcDNA-ZCCHC9). The cell viability, apoptosis, inflammatory cytokine levels, and fibrosis-associated protein expression in H9c2 cells were evaluated. ZCCHC9 promoter methylation were detected with methylation-specific PCR (MSP) assay. Then, rescue experiments were performed to explore whether APEX1 mediated cardiomyocyte functions by regulating ZCCHC9 expression. Furthermore, we explored whether the APEX1/ZCCHC9 axis regulated cardiomyocyte injury in AMI via the p38 MAPK signaling pathway. Additionally, an AMI rat model was established using the left anterior descending artery (LAD) ligation method and multipoint intramyocardial injection (5 points, 2 µL/point) of lentivirus (1 × 109 TU/mL) carrying scramble or si-APEX1 was conducted before modeling. The rats were euthanized four weeks after AMI modeling, and blood samples and myocardial tissues were harvested. The infarct area, cell apoptosis, inflammation, and fibrosis in myocardial tissues were detected. APEX1 was upregulated and ZCCHC9 was downregulated in blood samples of AMI patients compared with normal controls. APEX1 knockdown or ZCCHC9 overexpression attenuated Ang II-induced viability reduction, apoptosis, inflammation, and fibrosis in cardiomyocytes. APEX1 inhibited ZCCHC9 expression by promoting DNA methyltransferase 1 (DNMT1)-mediated ZCCHC9 promoter methylation. ZCCHC9 knockdown abolished the protective effects of APEX1 knockdown on Ang II-induced cardiomyocyte injury. APEX1 knockdown inhibited the p38 MAPK signal signaling, and anisomycin reversed the effect of APEX1 knockdown on cardiomyocyte functions. Additionally, APEX1 knockdown alleviated apoptosis, inflammation, and fibrosis in myocardial tissues of AMI rats. APEX1 knockdown attenuated Ang II-induced apoptosis, inflammation, and fibrosis in cardiomyocytes although promoting ZCCHC9 expression and inhibiting the p38 MAPK signaling pathway, thus relieving myocardial infarction, inflammation, and fibrosis in AMI rats.
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Caveolae are small membrane pits with fundamental roles in mechanotransduction. Several studies have shown that caveolae flatten out in response to increased membrane tension, thereby acting as a mechanosensitive membrane reservoir that buffers acute mechanical stress. Caveolae have also been implicated in the control of RhoA/ROCK-mediated actomyosin contractility at the rear of migrating cells. However, how membrane tension controls the organisation of caveolae and their role in mechanotransduction remains unclear. To address this, we systematically quantified protein-protein interactions of caveolin-1 in migrating RPE1 cells at steady state and in response to an acute increase in membrane tension using biotin-based proximity labelling and quantitative mass spectrometry. Our data show that caveolae are highly enriched at the rear of migrating RPE1 cells and that membrane tension rapidly and reversibly disrupts the caveolar protein coat. Membrane tension also detaches caveolin-1 from focal adhesion proteins and several mechanosensitive regulators of cortical actin including filamins and cortactin. In addition, we present evidence that ROCK and the RhoGAP ARHGAP29 associate with caveolin-1 in a manner dependent on membrane tension, with ARHGAP29 influencing caveolin-1 Y14 phosphorylation, caveolae rear localisation, and RPE1 cell migration. Taken together, our work uncovers a membrane tension-sensitive coupling between caveolae and the rear-localised F-actin cytoskeleton. This provides a framework for dissecting the molecular mechanisms underlying caveolae-regulated mechanotransduction pathways.
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Caveolina 1 , Movimento Celular , Proteômica , Humanos , Cavéolas/metabolismo , Caveolina 1/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Mecanotransdução Celular , Proteômica/métodos , Quinases Associadas a rho/metabolismoRESUMO
Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma, representing a global health problem for which a functional cure is difficult to achieve. The HBV core protein (HBc) is essential for multiple steps in the viral life cycle. It is the building block of the nucleocapsid in which viral DNA reverse transcription occurs, and its mediation role in viral-host cell interactions is critical to HBV infection persistence. However, systematic studies targeting HBc-interacting proteins remain lacking. Here, we combined HBc with the APEX2 to systematically identify HBc-related host proteins in living cells. Using functional screening, we confirmed that proteasome activator subunit 1 (PSME1) is a potent HBV-associated host factor. PSME1 expression was up-regulated upon HBV infection, and the protein level of HBc decreased after PSME1 knockdown. Mechanistically, the interaction between PSME1 and HBc inhibited the degradation of HBc by the 26S proteasome, thereby improving the stability of the HBc protein. Furthermore, PSME1 silencing inhibits HBV transcription in the HBV infection system. Our findings reveal an important mechanism by which PSME1 regulates HBc proteins and may facilitate the development of new antiviral therapies targeting PSME1 function.
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Context: One of the crucial steps in endodontic treatment is determining the working length (WL). There are various methods for performing this procedure, one of which is an electronic apex locator (EAL) measurement. Aims: The aim of this study was to determine the accuracy of six EALs, i.e.. Root ZX, Root ZX Mini, Propex PiXi, Innvopex-1, Woodpex III, and Raypex 6 for WL estimation in the mandibular first molars. Material and Method: The study included 180 root canals with symptomatic irreversible pulpitis, divided into six groups using different apex locators. WL determination was compared with intraoral periapical radiographs. Results were categorized as accurate, short, or long. The data were statistically analyzed. Results: ROOT ZX had an accuracy of 96.7%, Root ZX Mini had an accuracy of 93.3%, PiXi had an accuracy of 90.0%, Innvopex-1 had an accuracy of 90.0%, Woodpex III had an accuracy of 86.7%, and Raypex 6 had an accuracy of 83.4%, respectively. There was a statistically nonsignificant difference between groups (P < 0.05). Conclusion: Newly developed apex locators, such as the Innvopex-1, have shown accuracy comparable to well-established EALs like the Root ZX. This highlights the importance of conducting more extensive, large-scale research to confirm and validate their effectiveness.
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AIM: This study investigates the accuracy of an apex locator in mature and immature teeth with divergent root canals ex vivo. MATERIALS AND METHODS: Fifty extracted premolar teeth were utilized for the study, with 25 mature teeth (Nolla stage 9 or 10) and 25 immature teeth (Nolla stages ≤ 8). The discrepancies between the actual length (AL) and the electronic length (EL), measured using a Bingo 1020 apex locator, were compared and analyzed. Statistical analysis included Pearson's correlation analysis, a T-test for independent samples, and multiple linear regression. Statistical significance was set at p < 0.05. RESULTS: The difference between AL and EL in immature teeth was significantly higher than in mature premolar teeth. Nonetheless, patient gender or jaw type (upper/lower) did not affect the accuracy of electronic apex locator (EAL) measurements. CONCLUSION: EAL readings are less accurate in immature teeth than in mature teeth. Supplementary measures, such as radiographic length determination and wet-dry paper point tests, are required to confirm the working length for improved treatment outcomes and patient compliance.